KR102537985B1 - Monocyclic Compounds Useful as GPR120 Modulators - Google Patents

Abstract

Provided herein are compounds, compositions comprising them, and methods of modulating GPR120 activity and treating diseases mediated by GPR120 by administering such compounds and compositions.

Description

Monocyclic Compounds Useful as GPR120 Modulators

Cross reference to related patent application

This application claims priority from U.S. Provisional Application Serial No. 62/393,616, filed September 12, 2016, which application is incorporated herein by reference in its entirety.

technology field

The present invention provides compositions and methods for modulating the GPR120 receptor and relates generally to the fields of medical chemistry, medicine, pharmacology, molecular biology, and biology. Compounds that modulate the GPR120 receptor are useful for treating a variety of metabolic and inflammatory diseases, including but not limited to type 2 diabetes, obesity, hepatic steatosis, and Alzheimer's disease, and one or more symptoms of each disease.

Type 2 diabetes (T2D) is a chronic disease that results from the body's inefficient use of the insulin it produces. The state of hyperglycemia and insulin resistance observed in T2D typically results from being overweight and lack of exercise. As obesity and a sedentary lifestyle are increasing worldwide, the incidence of T2D is also rapidly increasing. The World Health Organization (WHO) estimates that over 300 million people worldwide have T2D, and over 1 million deaths per year can be directly attributed to T2D. WHO further predicts that diabetes-related deaths will increase by as much as 50% over the next 10 years. Current treatment strategies for T2D include treatment with agents that target the secretion or utilization of insulin. However, these strategies do not work or do not work well for all patients, and new strategies and agents are needed for the treatment of multiple aspects of T2D pathology.

GPR120, also known as free fatty acid receptor 4 (FFA4), is a 7-transmembrane-spanning G-protein coupled receptor activated by long-chain free fatty acids, including ω-3 fatty acids. GPR120 is expressed in a wide range of tissues and mediates multiple effects related to energy balance and inflammation. In enteroendocrine cells, activation of GPR120 leads to secretion of incretin glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), which in turn stimulates the release of insulin from pancreatic beta cells. Activation of GPR120 in adipocytes inhibits lipolysis while stimulating glucose uptake and adipogenesis. Activation of GPR120 in macrophages exerts an anti-inflammatory effect, inhibiting the release of cytokines including TNF-α and IL-6. In enteroendocrine cells and adipocytes, G120 signaling proceeds through Gq/11, whereas in macrophages, GPR120 signaling proceeds through the β-arrestin pathway. Dysfunction of GPR120 has been associated with diabetes and obesity in both mice and humans. Thus, GPR120 agonists have been used for the treatment of T2D and other metabolic diseases. (1-4)

Hepatic steatosis is a condition of inflammation and cellular damage associated with the accumulation of fat in the liver. When not related to alcohol consumption, the disease is known as non-alcoholic steatohepatitis (NASH). NASH is usually on the rise, can lead to cirrhosis or liver failure, and is often observed in people with obesity, glucose intolerance or dyslipidemia. Recent studies using wild-type and GPR120 deficient mice confirm a positive role for GPR120 in modulating lipid metabolism, triglyceride and diacylglycerol levels, and inflammatory markers. Consistent with these results, a study of children with NAFLD who were treated with the GPR120 agonist docosahexane (DHA) acid resulted in reduced liver damage and inflammatory macrophages and increased GPR120 hepatocyte expression (5a). ).

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with currently estimated 47 million cases worldwide and more than 130 million by 2050. Recently, activation of GPR120 exerts anti-inflammatory effects in immortalized hypothalamic neurons (6a), and GPR120 and another long-chain free fatty acid receptor, GPR40 (FFA1), control energy homeostasis and inflammation in the mouse hypothalamus (7a). ) was proved. NLRP3 inflammasome activity has been shown to contribute to pathology in APP/PS1 mice (8a). Omega-3 fatty acids block activation of the NLRP3 inflammasome in macrophages, thereby inhibiting down-activation of caspase-1 and maturation and release of interleukin-1 beta (IL-1 beta) (9a). Expression of the NLRP1 inflammasome is also upregulated in the brains of APP/PS1 mice, and Aβ induces NLRP1- and caspase-1-dependent pyroptosis in cultured cortical neurons from these animals ( 10a). Levels of inflammasome-activated caspase-1 are strongly enhanced in human brains with mild cognitive impairment and AD, and activation of NLRP1 in cultured human neurons induces axonal degeneration (11a). Thus, GPR120 agonists may be useful in AD, Parkinson's disease, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multi-system atrophy (MSA) and other disorders associated with neuroinflammation. It has a prospect as a disease-modifying treatment for the disease.

The present invention synthesizes or manufactures novel compounds, compositions of matter, particularly pharmaceutical compositions, compounds and compositions thereof, for modulating GPR120 and treating T2D, hepatic steatosis, Alzheimer's disease, and other diseases associated with metabolic dysfunction and inflammation. How to do it, and how to use them.

In certain aspects, the present invention provides compounds for modulating GPR120, compositions of matter (particularly pharmaceutical compositions), methods of synthesizing or preparing the compounds and compositions, and methods of using them.

Provided herein are compounds that modulate the GPR120 receptor, compositions comprising them, and methods of treating diseases by modulating the GPR120 receptor and administering such compounds and compositions.

A first aspect of the present invention relates to compounds of formula I comprising in various embodiments a bicyclic core element containing a 6-membered heteroatomic ring with 1-3 ring nitrogen atoms, and up to 3 ring substituents, as well as compounds of formula I , as well as Tautomers, isotopic isomers and stereoisomers of, and prodrugs of any of the foregoing, and pharmaceutically acceptable salts and solvates of all of the foregoing are provided.

Formula I

In the formula, each A is independently N or CH; B is N or CR ₂ provided that at least one of A or B is N; W is a covalent bond or O; each X is independently CH, CR ₃ , or N, where R ₃ is halogen, alkyl, alkoxy, or CN; Y is SO ₂ , CO, CH2, or -C(CH ₃ ) ₂ -, or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-(cyclopropano), CO, -(CO)CH ₂ -, - CH ₂ CH ₂ -, or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3 to 7-membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NHAc, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl or heterocyclyl group, or an optionally substituted aryl group. or a heteroaryl group. As used herein, amido includes carboxamido and sulfonamide groups.

The compounds of formula I stimulate the release of GLP-1, GIP and/or glucagon, inhibit the release of ghrelin, stimulate glucose uptake and/or exert an anti-inflammatory effect, thereby exerting a therapeutic effect in T2D. is considered to be In another aspect, provided herein is a method of agonizing GPR120 comprising contacting GPR120 with a compound or composition provided or disclosed herein.

In another aspect, provided herein is a method of modulating metabolism in a mammal comprising contacting GPR120 in a mammal with an amount of a compound provided herein effective to modulate metabolism in the mammal. In another aspect, provided herein is a method of modulating metabolism in a mammal comprising administering to the mammal an amount of a composition provided herein effective to modulate metabolism in the mammal.

In another aspect, provided herein is a method of reducing inflammation in a mammal comprising contacting GPR120 in a mammal with an amount of a compound provided herein effective to reduce inflammation. In another aspect, provided herein is a method of reducing inflammation in a mammal comprising administering to the mammal an amount of a composition provided herein effective to reduce inflammation.

In another aspect, provided herein is a method of reducing neuroinflammation in a mammal comprising contacting GPR120 in a mammal with an amount of a compound provided herein effective to reduce neuroinflammation. In another aspect, provided herein is a method of reducing neuroinflammation in a mammal comprising administering to the mammal an amount of a composition provided herein effective to reduce neuroinflammation.

In another aspect, provided herein is a method of treating diabetes, prediabetes or metabolic syndrome, or one or more symptoms of each of them, in a mammal comprising contacting GPR120 of the mammal with a therapeutically effective amount of a compound provided herein. Provided. In another aspect, provided herein is a method of treating diabetes, prediabetes or metabolic syndrome, or one or more symptoms of each thereof, in a mammal comprising administering to the mammal a therapeutically effective amount of a composition provided herein. .

In another aspect, provided herein is a method of treating steatohepatitis in a mammal comprising contacting GPR120 in the mammal with a therapeutically effective amount of a compound provided herein. In another aspect, provided herein is a method of treating steatohepatitis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition provided herein.

In another aspect, provided herein is a method of treating nonalcoholic steatohepatitis in a mammal comprising contacting GPR120 in the mammal with a therapeutically effective amount of a compound provided herein. In another aspect, provided herein is a method of treating non-alcoholic steatohepatitis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition provided herein.

In another aspect, provided herein is a method of treating a disorder associated with, leading to, or resulting from neuroinflammation in a mammal comprising contacting GPR120 of the mammal with a therapeutically effective amount of a compound provided herein. is provided. In another aspect, provided herein is a method of treating a disorder associated with, leading to, or resulting from neuroinflammation in a mammal comprising administering to the mammal a therapeutically effective amount of a composition provided herein. do.

In another aspect, described herein is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or multiple system atrophy, or each of them, comprising contacting GPR120 of a patient with a therapeutically effective amount of a compound provided herein. Methods of treating one or more symptoms of

In another aspect, provided herein is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or multiple system atrophy, or each one of them, comprising administering to a patient a therapeutically effective amount of a composition provided herein. Methods of treating the above symptoms are provided.

To assist the reader in understanding the invention, how it is made and used, and the benefits of the invention, the following usage and definitions are provided.

All technical and patent publications cited herein are incorporated herein by reference in their entirety.

All numerical representations, such as pH, temperature, time, concentration, and molecular weight, are approximations that can vary (+) or (-) by increments of, for example, 0.1 or 1, inclusive ranges. Therefore, all numerical designations may be interpreted by the reader as being preceded by the term "about". Likewise, the reagents described herein are merely illustrative; Generally, those skilled in the art will recognize that equivalents thereof are known in the art. As used in the specification and claims, terms referring to a single subject matter should be construed to include plural subject matter unless the context clearly dictates otherwise.

"Acyl" refers to a group of the formula -CO-R _x , wherein R _x is H or optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Examples of acyl groups include, for example, -CHO, -CO-Me, and -CO-Ph.

"Administering" or "administration of" (and grammatical equivalents in this phrase) a compound or composition drug to a patient refers to direct administration, which may be administration to the patient by a healthcare professional or self-administration; and / or refers to indirect administration, which may be the act of prescribing a drug. For example, a physician instructing a patient to self-administer a drug and/or providing a drug prescription to a patient is administering the drug to the patient.

“Alkoxy” refers to an alkyl group covalently bonded to an oxygen atom. Stated another way, an alkoxy group has the general structure -O-alkyl. C ₁ -C ₆ alkoxy groups are, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tertiary-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

“Alkenyl” refers to a straight-chain (or linear) or branched-chain hydrocarbon group containing at least one carbon-carbon double bond. C ₁ -C ₆ alkenyl groups include, for example, vinyl, allyl, and butenyl.

“Alkyl” refers to a straight-chain (or linear) or branched-chain hydrocarbon group. C ₁ -C ₆ alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

"Amino" refers to the monovalent radical -NR ^a R ^b , wherein R ^a and R ^b are independently hydrogen, alkyl, aryl or heteroaryl. The term "alkylamino" refers to the group -NR ^a R ^b , wherein R ^a is alkyl and R ^b is H or alkyl. In the case of a dialkylamino group, the alkyl moieties may be the same or different and may be combined to form a 3- to 8-membered ring together with the nitrogen atom to which each is attached. Thus, groups designated as -NR ^a R ^b are meant to include heterocyclyl groups such as piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

"Aryl" refers to a cyclic moiety comprising one or more monocyclic or fused ring aromatic systems containing 6 to 20 ring carbon atoms. Such moieties include any moiety having one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl.

"(C _m -C _n ), C _m -C _n , or C _m - _n " indicates the number of carbon atoms in a particular group preceded by such a symbol. For example, C ₁ -C ₆ alkyl refers to an alkyl group containing 1 to 6 carbon atoms.

"Carboxamide or carboxamido" refers to the monovalent radical -CO-NR ^a R ^b , wherein NRaRb is an "amino" group as defined above.

A "carrier" is a solid or liquid substance such as a polymer, solvent, suspending agent, absorbent, or adsorbent for pre-delivery or entrapment for subsequent delivery of a compound of the present invention. The carrier may be liquid or solid and is selected with the planned mode of administration in mind.

“Comprising” when used to define compounds, compositions and methods means that the recited elements may be present in conjunction with other materials or steps. “Consisting essentially of”, when used to define compounds, compositions and methods, means that the recited elements are not present together with other elements that could materially affect the basic and novel characteristics of the claimed invention. means it may not "Consisting of" means only the recited elements. Embodiments defined by each of these connection terms are within the scope of this invention.

"Cycloalkyl", unless stated otherwise, refers to cyclic versions of "alkyl", "alkenyl" and "alkynyl" in which all ring atoms are carbon. "Cycloalkyl" refers to a mono- or polycyclic group. "Cycloalkyl" can form a bridged ring or a spiro ring. Cycloalkyl groups can have one or more double or triple bond(s). A typical cycloalkyl group has 3 to 8 ring atoms. Examples of cycloalkyls are cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl.

“Halogen” or “halo” by itself or as part of another substituent represents a fluorine, chlorine, bromine, or iodine atom, unless stated otherwise.

"Heteroaryl" refers to a monocyclic aromatic system having 5 or 6 ring atoms, or a fused ring bicyclic aromatic system having 8 to 20 atoms, wherein the ring atoms are C, O, S, SO, SO ₂ , or N, and at least one of the ring atoms is a heteroatom, ie O, S, SO, SO ₂ , or N. Heteroaryl groups include, for example, acridinyl, azocynyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetra zolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromanyl, cinolinyl, dithiazinyl, furanyl, furanyl xanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, Isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl , phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, Pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinu Clidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thiaantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thie neumidazolyl, thiophenyl, triazinyl and xanthenyl. Unless otherwise indicated, the arrangement of heteroatoms in a ring can be any arrangement permitted by the bonding nature of the constituent ring atoms.

"Heterocyclyl" or heterocyclic means provided that at least a portion thereof is not aromatic and at least one of the carbon atoms of the ring system is replaced by a heteroatom selected from O, S, SO, SO ₂ , P, or N. Represents a cyclic or fused ring polycyclic cycloalkyl group. Examples of heterocyclyl groups include, but are not limited to, imidazolinyl, morpholinyl, piperidinyl, piperidin-2-oneyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-oneyl. , tetrahydrofuranyl, tetrahydropyranyl, and tetrahydroimidazo [4,5-c]pyridinyl.

"Pharmaceutically acceptable salt" refers to a salt of an active compound prepared with a relatively non-toxic acid or base, depending on the particular acidic or basic nature of the compounds described herein. When the compounds of this invention contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and the like. Salts derived from pharmaceutically acceptable organic bases include substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-di Methylaminoethanol, ethanolamine, ethylenediamine, N-ethylmoproline, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid. derived from, as well as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and salts derived from relatively non-toxic organic acids such as Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the present invention may contain both basic and acidic functionality that allows the compound to be converted into either a base or an acid addition salt.

"Pharmaceutically acceptable excipient, carrier, or diluent" refers to an excipient, carrier, or diluent that is generally safe, non-toxic, and which is not biologically or otherwise undesirable, for human pharmaceutical as well as veterinary use. It includes an excipient, carrier, or diluent that is also acceptable. A "pharmaceutically acceptable excipient, carrier, or diluent" includes both one and one or more of such excipients, carriers, or diluents.

“Reduction” or “suppression” of a symptom or symptoms (and grammatical equivalents in this phrase) of a pathological condition or disease refers to reducing the severity or frequency of the symptom(s), or eliminating the symptom(s) .

"Subject", used interchangeably with "individual" and "patient" herein, refers to a vertebrate, typically a mammal, and usually a human. Mammals include, but are not limited to, mice, rats, rabbits, apes, cows, sheep, pigs, dogs, cats, farm animals, sport animals, pets, horses, and primates.

“Substituted” refers to a group as defined herein in which one or more bonds to carbon(s) or hydrogen(s) are replaced by bonds to non-hydrogen and non-carbon atoms, and “substituents” are Although not limited to, halogen atoms; oxygen atoms of groups such as hydroxyl groups, alkoxy groups, aryloxy, and acyloxy groups; sulfur atoms of groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; such as nitro, -NH ₂ , alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, alkoxyaminos, hydroxyaminos, acylaminos, sulfonylaminos, N-oxides, imides, and enamines. a nitrogen atom of a group; and other heteroatoms of various other groups. “Substituent” also means that one or more bonds to a carbon(s) or hydrogen(s) atom are oxygen of oxo, acyl, amido, alkoxycarbonyl, aminocarbonyl, carboxyl, and ester groups; groups such as imines, oximes, hydrazones, and groups that are replaced by higher order bonds (such as double- or triple-bonds) to heteroatoms such as nitrogen of groups such as nitriles. “Substituent” further also includes groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by bonds to cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. For cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, "substituent" still further includes substituted and unsubstituted alkyl groups. Other substituents include ethynyl, vinyl, carboxyl and its esters and amides, hydroxymethyl, and methyl. Another "substituent" is trifluoromethyl or other fluoroalkyl groups and other groups containing these groups. Two substituents on the same or adjacent carbon atoms together with the carbon atoms to which they are attached form a heterocyclic or cycloalkyl group. Typically, a particular group may have 0 (unsubstituted), 1, 2 or 3 substituents. As will be clear to those skilled in the art, substitution with substituents will not result in polymeric moieties greater than 1000 molecular weight.

"Sulphonamide or sulfonamido" refers to the monovalent radical -SO ₂ -NR ^a R ^b , wherein NRaRb is an "amino" group as defined above.

A "therapeutically effective amount" is an amount administered to a patient suffering from a disease mediated by GPR120 that is sufficient to achieve a beneficial or desired result. A therapeutically effective amount can be administered in one or more administrations, applications, or dosages.

“Treating” a condition or patient or “treating” a condition or patient refers to taking steps to obtain a beneficial or desired result, including a clinical result such as reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of a disease mediated by GPR120; reduction of the severity of such disease; delay or slowing of such disease progression; amelioration, alleviation, or stabilization of such conditions; or other beneficial outcomes.

“Reduction” or “suppression” of a symptom or symptoms of a pathological condition or disease (and grammatical equivalents of this phrase) refers to reducing the severity or frequency of the symptom(s), or eliminating the symptom(s).

Thus, in a first aspect, the invention relates to a compound of formula I or its tautomers, isotopic isomers and stereoisomers, and prodrugs of any of the foregoing, and pharmaceutically acceptable salts and solvents of all of the foregoing. Freight is provided:

Formula I

In the above formula,

each A is independently N or CH; B is N or CR ₂ provided that at least one of A or B is N; W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy, or CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ -, or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, -CH ₂ CH ₂ - , or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , -NH-acyl, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl, or heterocyclyl group, or an optional An aryl or heteroaryl group substituted with

In one preferred embodiment, the central heterocycle is a di- or trisubstituted pyrimidine comprising an optionally substituted 5,6- or 6,6-bicyclic fused ring system, such as but not limited to Formula II :

Formula II

In the formula, W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy or CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ - or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, -CH ₂ CH ₂ - , or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NHAc, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl, or heterocyclyl group, or an optionally substituted an aryl or heteroaryl group.

In a more preferred embodiment of formula II , W is O and R ₁ is an optionally substituted cycloalkyl or heterocyclyl group. Examples of specific preferred cycloalkyl and heterocyclyl groups are given below, wherein R ₁₁ is attached to W. R ₁₂ and R ₁₃ are independently H, CH ₃ , CF ₃ , or F.

In another more preferred embodiment of Formula II , W is O and R ₁ is an optionally substituted aryl or heteroaryl group. Examples of specific preferred aryl and heteroaryl groups are provided below, wherein R ₁₁ is attached to W, R ₁₅ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN, and R ₁₆ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , CN, NHCOR ₁₄ , or N(CH ₃ )COR ₁₄ , where R ₁₄ is alkyl, cycloalkyl, aryl or heteroaryl.

In another more preferred embodiment of Formula II , W is O and R ₁ is an optionally substituted fused bicyclic aryl or heteroaryl group. Examples of specific preferred fused bicyclic aryl or heteroaryl groups are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN am.

In another more preferred embodiment of Formula II , W is a covalent bond and R ₁ is an optionally substituted bicyclic amine. Examples of specific preferred bicyclic amines are given below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ or CN.

In a second preferred embodiment, the central heterocycle is a di- or trisubstituted pyrimidine comprising an optionally substituted 5,6- or 6,6-bicyclic fused ring system, such as but not limited to formula III am:

Formula III

In the formula, W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy, CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ -, or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, -CH ₂ CH ₂ - , or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NHAc, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl, or heterocyclyl group, or an optionally substituted an aryl or heteroaryl group.

In a more preferred embodiment of formula III , W is O and R ₁ is an optionally substituted cycloalkyl or heterocyclyl group. Examples of specific preferred cycloalkyl and heterocyclyl groups are given below, wherein R ₁₁ is attached to W. R ₁₂ and R ₁₃ are independently H, CH ₃ , CF ₃ , or F.

In another more preferred embodiment of Formula III , W is O and R ₁ is an optionally substituted aryl or heteroaryl group. Examples of specific preferred aryl and heteroaryl groups are provided below, wherein R ₁₁ is attached to W, R ₁₅ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN, and R ₁₆ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , CN, NHCOR ₁₄ or N(CH ₃ )COR ₁₄ , where R ₁₄ is alkyl, cycloalkyl, aryl or heteroaryl.

In another more preferred embodiment of Formula III , W is O and R ₁ is an optionally substituted fused bicyclic aryl or heteroaryl group. Examples of specific preferred fused bicyclic aryl or heteroaryl groups are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN am.

In another more preferred embodiment of Formula III , W is a covalent bond and R ₁ is an optionally substituted bicyclic amine. Examples of specific preferred bicyclic amines are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN.

In a third preferred embodiment, the central heterocycle is a di- or trisubstituted pyridine comprising an optionally substituted 5,6- or 6,6-bicyclic fused ring system, such as but not limited to formula IV :

Formula IV

In the formula, W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy, CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ -, or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, -CH ₂ CH ₂ - , or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NHAc, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl, or heterocyclyl group, or an optionally substituted an aryl or heteroaryl group.

In a more preferred embodiment of formula IV , W is O and R ₁ is an optionally substituted cycloalkyl or heterocyclyl group. Examples of specific preferred cycloalkyl and heterocyclyl groups are given below, wherein R ₁₁ is attached to W. R ₁₂ and R ₁₃ are independently H, CH ₃ , CF ₃ , or F.

In another more preferred embodiment of Formula IV , W is O and R ₁ is an optionally substituted aryl or heteroaryl group. Examples of specific preferred aryl and heteroaryl groups are given below, wherein R ₁₁ is attached to W, R ₁₅ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ or CN, and R ₁₆ is H, halogen , alkyl, CF ₃ , OCH ₃ , OCF ₃ , CN, NHCOR ₁₄ , N(CH ₃ )COR ₁₄ , wherein R ₁₄ is alkyl, cycloalkyl, aryl or heteroaryl.

In another more preferred embodiment of Formula IV , W is O and R ₁ is an optionally substituted fused bicyclic aryl or heteroaryl group. Examples of specific preferred fused bicyclic aryl or heteroaryl groups are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN am.

In another more preferred embodiment of Formula IV , W is a covalent bond and R ₁ is an optionally substituted bicyclic amine. Examples of specific preferred bicyclic amines are given below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ or CN.

In a fourth preferred embodiment, the central heterocycle is a disubstituted pyrazine comprising an optionally substituted 5,6- or 6,6-bicyclic fused ring system, such as but not limited to formula V :

Expression V

In the formula, W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy or CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ - or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, or -CH ₂ CH ₂ -, -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group.

In a more preferred embodiment of formula V , W is O and R ₁ is an optionally substituted cycloalkyl or heterocyclyl group. Examples of specific preferred cycloalkyl and heterocyclyl groups are given below, wherein R ₁₁ is attached to W. R ₁₂ and R ₁₃ are independently H, CH ₃ , CF ₃ , or F.

In another more preferred embodiment of Formula V , W is O and R ₁ is an optionally substituted aryl or heteroaryl group. Examples of specific preferred aryl and heteroaryl groups are provided below, wherein R ₁₁ is attached to W, R ₁₅ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN, and R ₁₆ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , CN, NHCOR ₁₄ , or N(CH ₃ )COR ₁₄ , where R ₁₄ is alkyl, cycloalkyl, aryl or heteroaryl.

In another more preferred embodiment of Formula V , W is O and R ₁ is an optionally substituted fused bicyclic aryl or heteroaryl group. Examples of specific preferred fused bicyclic aryl or heteroaryl groups are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN am.

In another more preferred embodiment of Formula V , W is a covalent bond and R ₁ is an optionally substituted bicyclic amine. Examples of specific preferred bicyclic amines are given below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ or CN.

In a fifth preferred embodiment, the central heterocycle is a di- or trisubstituted triazole comprising an optionally substituted 5,6- or 6,6-bicyclic fused ring system, such as but not limited to formula VI: :

Formula VI

In the formula, W is a covalent bond or O; each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy or CN; Y is SO ₂ , CO, CH ₂ , -C(CH ₃ ) ₂ - or -CH(CH ₃ )-; Z is -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -C(CH ₂ CH ₂ )-, CO, -(CO)CH ₂ -, -CH ₂ CH ₂ - , or -CHCH-; R ₁ is an optionally substituted alkyl group, an optionally substituted 3-7 membered cycloalkyl or heterocyclyl group, or an optionally substituted aryl or heteroaryl group; R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NHAc, an optionally substituted alkyl group, an optionally substituted amido group, an optionally substituted cycloalkyl, or heterocyclyl group, or an optionally substituted an aryl or heteroaryl group.

In a more preferred embodiment of Formula VI , W is O and R ₁ is an optionally substituted cycloalkyl or heterocyclyl group. Examples of specific preferred cycloalkyl and heterocyclyl groups are given below, wherein R ₁₁ is attached to W. R ₁₂ and R ₁₃ are independently H, CH ₃ , CF ₃ , or F.

In another more preferred embodiment of Formula VI , W is O and R ₁ is an optionally substituted aryl or heteroaryl group. Examples of specific preferred aryl and heteroaryl groups are provided below, wherein R ₁₁ is attached to W, R ₁₅ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN, and R ₁₆ is H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , CN, NHCOR ₁₄ , or N(CH ₃ )COR ₁₄ , where R ₁₄ is alkyl, cycloalkyl, aryl or heteroaryl.

In another more preferred embodiment of Formula VI , W is O and R ₁ is an optionally substituted fused bicyclic aryl or heteroaryl group. Examples of specific preferred fused bicyclic aryl or heteroaryl groups are provided below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ , or CN am.

In another more preferred embodiment of Formula VI , W is a covalent bond and R ₁ is an optionally substituted bicyclic amine. Examples of specific preferred bicyclic amines are given below, wherein R ₁₁ is attached to W and R ₁₅ and R ₁₇ are independently H, halogen, alkyl, CF ₃ , OCH ₃ , OCF ₃ or CN.

In another aspect, a compound provided herein is selected from:

Certain compounds of the present invention are synthesized as outlined below. Other compounds of the present invention may be obtained by these and other methods exemplified in the Examples section below, or by the use of starting materials, other reagents, and/or process conditions (i.e., reaction temperature, time, mole ratios of reactants, solvents, pressures, etc.) It can be synthesized by adjusting methods known to those skilled in the art upon appropriate substitution.

In the case of compounds of the invention containing one or more chiral centers, such compounds may be prepared or isolated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomerically-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the compounds provided and utilized herein unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated using, for example, chiral column chromatography, chiral dissolution reagents, and the like.

In another aspect, the present invention provides a composition, ie a pharmaceutical formulation, comprising a compound of the present invention and at least one pharmaceutically acceptable excipient. In general, a compound of the present invention may be formulated for administration to a patient by any accepted mode of administration. Therefore, the invention provides solid and liquid formulations of the compounds of the invention. A variety of formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences , ^18th ed., Mack Publishing Co. reference.

Typically, a compound of the present invention will be administered as a pharmaceutical composition by one of the following routes: oral, systemic (eg transdermal, intranasal or suppository), or parenteral (eg intramuscular, intravenous or subcutaneous) administration. . Compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release preparations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

A pharmaceutical dosage form of a compound of the present invention may be prepared by any of the methods well known in the art, for example conventional mixing, sifting, dissolving, melting, granulating, capping, tableting, suspending, It can be prepared by extrusion, spray-drying, levigating, emulsifying, (nano/micro-) encapsulation, entrapment, or lyophilization processes. As noted above, the compositions of the present invention may contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.

Pharmaceutical formulations have been developed specifically for drugs with poor bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, i.e., reducing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles ranging in size from 10 to 1,000 nm in which the active substance is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 discloses a pharmaceutical formulation wherein a drug substance is milled into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to provide a pharmaceutical formulation that exhibits remarkably high bioavailability. describe the manufacture of In some embodiments, the compounds of the invention are formulated as such.

Compositions generally consist of a compound of the present invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipients can be any solid, liquid, semi-solid or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk powder, and the like. there is. Liquid and semi-solid excipients may be selected from a variety of oils, including glycerol, propylene glycol, water, ethanol and oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

The composition may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may include, for example, a metal or plastic foil, such as a blister pack, or glass, and a rubber stopper, as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

The amount of compound in the formulation may vary within the full range used by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01 to 99% by weight of a compound of the present invention, based on the total formulation, the balance being one or more suitable pharmaceutical excipients. Generally, the compound is present at a level of about 1 to 80% by weight.

In another aspect, the invention provides a method of producing a therapeutic effect of GPR120 by contacting a therapeutically effective amount of a compound or composition of the invention with GPR120 in need thereof. In one embodiment, the therapeutic effect is produced in cells. In other embodiments, contacting is performed in vitro or in vivo.

In another aspect, provided herein is a method of treating type 2 diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or composition of the present invention. In one embodiment, the subject is a human.

All technical and patent publications cited herein are incorporated herein by reference in their entirety.

The invention described in the Content and Detailed Description of the Invention is exemplified by the following examples and is not limited thereto. Examples 1-146 illustrate certain compounds of the invention and methods for their synthesis. Examples 147 and 148 illustrate how the ability of compounds of the invention to activate the GPR120 receptor can be measured in a biological assay.

synthesis example

Example One

Synthesis of Compound 1

Step 1.

Saccharin (10.0 g, 54.6 mmol) was added slowly to a solution of LiAlH ₄ (2.24 g, 59.0 mmol) in 300 mL of THF at 0 °C. The reaction mixture was stirred at 15° C. for 3 h under an inert atmosphere. Upon completion EtOAc (100 mL) was added slowly followed by 10% H ₂ SO ₄ (100 mL). The organic layer was separated, washed with 100 mL of 5% sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 1 (4.4 g, 97%).

Step 2.

To a solution of 1 (97.0 mg, 0.57 mmol) in DMF (4 mL) at 0 °C was added NaH (13.9 mg, 0.58 mmol). The mixture was stirred at 0 °C for 30 minutes. Dichloropyrimidine 2 (100 mg, 0.48 mmol, 1.0 eq) was added and the solution was warmed to 15 °C and stirred 15 h. The resulting mixture was poured into ice water (w/w = 1/1, 20 mL) and stirred for 10 minutes. The aqueous phase was extracted with EtOAc (30 mL), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 3 (120 mg, 72%).

Step 3.

A solution of 3 (200 mg, 0.71 mmol), pyridin-3-ol (81 g, 852 mmol), CsF (215 mg, 1.42 mmol) and Cs ₂ CO ₃ (462 mg, 1.42 mmol) in DMSO (3 mL) was degassed and then heated to 80° C. for 16 h under an inert atmosphere. Upon consumption of the starting material the reaction mixture was poured into water (50 mL). The mixture was extracted with EtOAc (60 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting material was purified by preparative HPLC to give 70 mg (29%) of Compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.56 (d, 1H), 8.52-8.46 (m, 2H), 8.06 (d, 1H), 7.88-7.82 (m, 1H), 7.81-7.68 (m , 3H), 7.51 (dd, 1H), 7.09 (d, 1H), 5.18 (s, 2H); LCMS (ESI+): m/z 341 (M+H).

Example 2

Synthesis of compound 2

Step 1.

To a solution of 2-cyanobenzoic acid (1.50 g, 10.2 mmol) in THF (15 mL) was added MeLi (1M, 204 mL) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 2 h, warmed to 30 °C and stirred for an additional 18 h. Upon completion water (300 mL) was added and the mixture was extracted with EtOAc (300 mL). The organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether; EtOAc = 1:1) gave 4 (400 mg, 22%).

step. 2

BH ₃ .THF (1M, 5.7 mL) was added dropwise to a solution of 3,3-dimethylphthalimidine (230 mg, 1.43 mmol) in THF (6 mL) under inert atmosphere and the resulting mixture was stirred at 80° C. for 16 h. Stirred. Upon completion MeOH (4 mL) was added and the reaction mixture was stirred 5 h. Concentration under reduced pressure and purification by pre-TLC (silica gel, petroleum ether: EtOAc = 3:1) gave 5 .

Compound 2 was synthesized from 5 in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.79 (s, 1H), 8.67-8.66 (d, 1H), 8.27-8.25 (d, 1H), 8.08-8.06 (d, 1H), 7.77-7.74 (m, 1H), 7.30-7.28 (m, 1H), 6.60-6.58 (d, 1H), 4.85 (s, 2H), 1.34 (s, 6H); LCMS (ESI): m/z 319.1 (M+H).

Example 3

Synthesis of compound 3

Compound 3 was synthesized in a similar manner to compound 1 . LCMS (ESI): m/z 375.0 (M+H).

Example 4

Synthesis of compound 4

Compound 4 was synthesized in a similar manner to compound 1 . LCMS (ESI): m/z 375.1 (M+H).

Example 5

Synthesis of compound 5

Compound 5 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.55-8.50 (m, 4H), 7.79-7.77 (d, 1H), 7.67 (s, 2H), 7.53-7.51 (d, 1H), 7.08-7.07 (d, 1H), 5.7 (s, 2H), 3.98 (s, 3H); LCMS (ESI): m/z 405.0 (M+H).

Example 6

Synthesis of compound 6

Compound 6 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.87 (s, 1H), 8.70-8.69 (d, 1H), 8.59-8.57 (d, 1H), 8.18-8.16 (d, 1H), 8.05-8.03 (d, 1H), 7.88-7.82 (m, 3H), 7.72-7.71 (d, 1H), 7.41-7.40 (d, 1H), 1.64 (s, 6H); LCMS (ESI): m/z 369.1 (M+H).

Example 7

Synthesis of compound 7

Compound 7 was synthesized in a similar manner to compound 1 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.42 (d, J =5.52 Hz, 1H), 7.92 (d, J =7.78 Hz, 1H), 7.86-7.79 (m, 1H), 7.75-7.65 ( m, 2H), 7.03 (d, J =5.77 Hz, 1H), 5.16 (s, 2H), 4.91-4.88 (m, 1H), 3.27-3.18 (m, 2H), 2.93-2.86 (m, 2H) ; LCMS (ESI): m/z 354.0 (M+H).

Example 8

Synthesis of compound 8

Compound 8 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.93-8.92 (d, 1H), 8.71-8.70 (d, 1H), 8.57-8.56 (d, 1H), 8.30-8.29 (d, 1H), 8.06 -8.04 (d, 1H), 7.89-7.85 (m, 2H), 7.80-7.78 (d, 1H), 7.72-7.70 (m, 1H), 7.22-7.20 (d, 1H), 5.68-5.64 (m, 1H), 1.57-1.55 (d, 3H); LCMS (ESI): m/z 355.0 (M+H).

Example 9

Synthesis of compound 9

Compound 9 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.09-9.08 (d, 1H), 8.90-8.89 (d, 1H), 8.80-8.79 (d, 1H), 8.63-8.62 (d, 1H), 8.48 (s, 1H), 8.30-8.28 (m, 2H), 8.08-8.06 (m, 1H), 7.64-7.62 (m, 1H), 4.97 (s, 2H); LCMS (ESI): m/z 306.1 (M+H).

Example 10

Synthesis of compound 10

Compound 10 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.82-8.81 (d, 1H), 8.60-8.57 (m, 2H), 8.53-8.52 (d, 1H), 8.30-8.29 (d, 1H), 8.21 -8.19 (d, 1H), 7.82-7.81 (d, 1H), 7.72-7.69 (m, 1H), 7.58-7.56 (m, 1H), 4.98 (s, 2H); LCMS (ESI): m/z 306.1 (M+H).

Example 11

Synthesis of compound 11

Compound 11 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.78-8.65 (m, 2H), 8.53 (d, J =4.52 Hz, 1H), 8.07-7.99 (d, J =7.53 Hz, 1H), 7.65- 7.49 (m, 2H), 7.32-7.23 (m, 2H), 6.96 (d, J =5.52 Hz, 1H), 4.87 (s, 2H), 3.85 (s, 3H); LCMS (ESI): m/z 335.1 (M+H).

Example 12

Synthesis of compound 12

Compound 12 was synthesized in a similar manner to compound 1 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.75-8.63 (m, 2H), 8.58-8.42 (m, 1H), 8.07-7.92 (m, 1H), 7.70 (d, J =8.53 Hz, 1H ), 7.55 (dd, J=8.41, 4.64 Hz, 1H), 7.23 (s, 1H), 7.14-7.04 (m, 1H), 6.93 (d, J =5.77 Hz, 1H), 4.87 (s, 2H) , 3.93–3.80 (m, 3H); LCMS (ESI): m/z 335.0 (M+H).

Example 13 and 14

Synthesis of compounds 13 and 14

Step 1.

Isoindoline (175 mg, 1.47 mmol) and diisopropylethylamine (260 mg, 2.01 mmol) were dissolved in DMSO (4 mL). The resulting mixture was warmed up to 30 °C and 1,4-dichloroprimidine (199 mg, 1.34 mmol) was added. Upon completion water (30 mL) was added and the resulting mixture was extracted with EtOAc (60 mL). The organic phase was washed with brine, filtered and concentrated under reduced pressure to give a mixture of 6 and 6A (440 mg), which was used in the next step without further purification.

Step 2.

A mixture of 6 and 6A (240 mg, 0.31 mmol), pyridyl-3-ol (48 mg, 0.51 mmol), Cs ₂ CO ₃ (202 mg, 0.62 mmol), and CsF (94 mg) in DMSO (5 mL) , 0.62 mmol) was stirred at 120°C for 2 h. Upon completion water (30 mL) was added and the resulting mixture was extracted with EtOAc (60 mL). The organic phase was washed with brine, filtered and concentrated under reduced pressure. The regioisomer was purified and separated by pre-HPLC to give compound 13 (20 mg, 21%) and compound 14 (9 mg, 9%), both of which were white solids. compound 13. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.595-8.59 (d, 1H), 8.50-8.49 (d, 1H), 8.10-8.08 (d, 1H), 7.84-7.82 (d, 1H) , 7.58 (m, 1H), 7.57-7.37 (m, 2H), 7.32-7.30 (m, 2H), 6.50-6.48 (d, 1H), 4.78-4.70 (d, 4H); LCMS (ESI): m/z : 291.2 (M+H). compound 14. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.667-8.661 (d, 1H), 8.56-8.55 (d, 1H), 8.37-8.36 (d, 1H), 7.93-7.90 (d, 1H), 7.64-7.60 (m, 1H), 7.35-7.27 (m, 4H), 6.42-6.40 (d, 1H), 4.79 (s, 2H), 4.50 (s, 2H); LCMS (ESI): m/z 291.2 (M+H).

Example 15

Synthesis of compound 15

A mixture of 3 (40 mg, 0.14 mmol), pyridin-4-ol (16 mg, 0.170 mmol), and Cs ₂ CO ₃ (92 mg, 0.28 mmol) in DMF (2 mL) was stirred at 45 °C for 1.5 h. . Upon completion the mixture was filtered and concentrated under reduced pressure. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave 10 mg (21%) of compound 15 as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.85-8.83 (d, 2H), 8.75-8.74 (d, 1H), 8.08-8.06 (d, 1H), 7.89-7.85 (m, 1H), 7.77- 7.70 (m, 2H), 7.23–7.19 (m, 1H), 6.37–6.35 (d, 2H), 5.33 (s, 2H); LCMS (ESI): m/z 341.0 (M+H).

Example 16

Synthesis of compound 16

Compound 16 was synthesized in a similar manner to compound 15 . ¹ H NMR : (DMSO- d ₆ , 400 MHz) δ 8.45-8.44 (d, 1H), 8.04-8.03 (d, 1H), 7.83-7.73 (m, 1H), 7.71-7.67 (m, 2H), 7.44-7.40 (m, 2H), 7.24-7.22 (m, 3H), 7.06-7.05 (d, 1H), 5.15 (s, 2H); LCMS (ESI): m/z 340.0 (M+H).

Example 17

Synthesis of compound 17

Compound 17 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.53-8.52 (d, 1H), 8.50-8.49 (d, 1H), 8.04-8.02 (d, 1H), 7.85-7.81 (t, 1H), 7.72 -7.69 (m, 2H), 7.67-7.59 (t, 1H), 7.09-7.07 (d, 1H), 5.16 (s, 2H), 2.43 (s 3H); LCMS (ESI): m/z 355 (M+H).

Example 18

Synthesis of compound 18

Compound 18 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.02 (d, 1H), 8.55-8.54 (d, 1H), 8.51 (d, 1H), 8.01-7.99 (d, 1H), 7.88-7.87 (d , 1H), 7.84-7.82 (t, 1H), 7.72-7.68 (m, 2H), 7.13-7.12 (d, 1H), 5.09 (s, 2H), 2.83 (s, 3H); LCMS (ESI): m/z 355 (M+H).

Example 19

Synthesis of compound 19

Compound 19 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.79 (s, 1H), 8.60 (s, 1H), 8.55-8.53 (d, 1H), 8.23 (s, 1H), 8.04-8.02 (d, 1H) ), 7.84-7.82 (t, 1H), 7.73-7.67 (m, 2H), 7.10-7.09 (d, 1H), 5.17 (s, 2H), 2.45 (s, 3H); LCMS (ESI): m/z 355 (M+H).

Example 20

Synthesis of compound 20

Compound 20 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.44-8.43 (d, 1H), 8.05-8.03 (d, 1H), 7.83-7.81 (t, 1H), 7.73-7.69 (m, 2H), 7.59 -7.57 (d, 1H), 7.42-7.40 (m, 2H), 7.33-7.71 (m, 1H), 7.08-7.07 (d, 1H), 5.17 (s, 2H); LCMS (ESI): m/z 374 (M+H).

Example 21

Synthesis of compound 21

Compound 21 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.48-8.47 (d, 1H), 8.08-8.04 (d, 1H), 7.84-7.82 (t, 1H), 7.75-7.68 (m, 2H), 7.49 -7.47 (d, 2H), 7.32-7.30 (d, 1H), 7.10-7.08 (d, 1H), 5.16 (s, 2H); LCMS (ESI): m/z 374 (M+H).

Example 22

Synthesis of compound 22

Compound 22 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.49-8.48 (d, 1H), 8.07-8.05 (d, 1H), 7.85-7.75 (m, 1H), 7.73-7.70 (m, 2H), 7.47 -7.43 (m, 2H), 7.35 (d, 1H), 7.27 (d, 1H), 7.09-7.08 (d, 1H), 5.18 (s, 2H); LCMS (ESI): m/z 374.0 (M+H).

Example 23

Synthesis of compound 23

Compound 23 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.49-8.48 (d, 1H), 8.06-8.04 (d, 1H), 7.84-7.82 (m, 1H), 7.75-7.68 (m, 2H), 7.41 -7.39 (m, 1H), 7.14-7.06 (m, 3H), 6.93 (bs, 1H), 5.17 (s, 2H), 3.01 (s, 6H); LCMS (ESI): m/z 383.0 (M+H).

Example 24

Synthesis of Compound 24

Compound 24 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 10.06 (s, 1H), 8.47-8.46 (d, 1H), 8.07-8.05 (d, 1H), 7.87-7.83 (m, 1H), 7.75-7.71 (m, 2H), 7.55 (s, 1H), 7.37-7.33 (m, 2H), 7.09-7.08 (d, 1H), 6.91-6.90 (d, 1H), 5.19 (s, 2H), 2.04 (s) , 3H); LCMS (ESI): m/z 397.0 (M+H).

Example 25

Synthesis of compound 25

Compound 25 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.10 (s, 1H), 8.91 (s, 2H), 8.54-8.52 (d, 1H), 8.06-8.04 (d, 1H), 7.86-7.82 (m , 1H), 7.74-7.68 (m, 2H), 7.12-7.10 (d, 1H), 5.17 (s, 2H); LCMS (ESI): m/z 342.0 (M+H).

Example 26

Synthesis of compound 26

Compound 26 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.91-8.90 (d, 1H), 8.52-8.50 (d, 1H), 8.34-8.33 (d, 1H), 8.09-7.99 (m, 3H), 7.84 -7.65 (m, 4H), 7.12-7.11 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 391.0 (M+H).

Example 27

Synthesis of compound 27

Compound 27 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.89-8.87 (d, 1H), 8.57-8.55 (d, 1H), 8.28-8.26 (d, 1H), 8.23-8.21 (d, 1H), 8.11 -8.09 (d, 1H), 7.87 (m, 1H), 7.79 (m, 1H), 7.73-7.68 (m, 2H), 7.47 (m, 1H), 7.42-7.40 (d, 1H), 6.31-6.29 (d, 1H), 5.32 (s, 2H); LCMS (ESI): m/z 391.0 (M+H).

Example 28

Synthesis of compound 28

Compound 28 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.71 (s, 1H), 8.59-8.55 (m, 2H), 8.27-8.27 (d, 1H), 7.87-7.85 (m, 1H), 7.76-7.71 (m, 2H), 7.64 (d, 1H), 4.99 (s, 2H); LCMS (ESI): m/z 305.0 (M+H).

Example 29

Synthesis of compound 29

Compound 29 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.91-8.89 (d, 1H), 8.71-8.69 (d, 1H), 8.27 (d, 1H), 8.05-8.03 (d, 1H), 7.85-7.83 (d, 1H), 7.78-7.72 (m, 2H), 7.64-7.62 (d, 1H), 7.32 (m, 1H), 7.24-7.22 (d, 1H), 7.00-6.99 (d, 1H), 6.80 -6.79 (d, 1H), 5.28 (s, 2H); LCMS (ESI): m/z 363.0 (M+H).

Example 30

Synthesis of compound 30

Compound 30 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.32 (s, 1H), 9.23-9.21 (d, 1H), 8.83-8.81 (d, 2H), 8.06-8.04 (d, 1H), 7.75-7.68 (m, 2H), 7.25-7.17 (m, 3H); LCMS (ESI): m/z 364.0 (M+H).

Example 31

Synthesis of compound 31

Compound 31 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.14 (s, 1H), 8.77-8.72 (m, 2H), 8.09-8.07 (d, 1H), 7.83-7.81 (d, 1H), 7.73-7.68 (m, 3H), 7.35-7.13 (d, 1H), 5.33 (s, 2H); LCMS (ESI): m/z 364.0 (M+H).

Example 32

Synthesis of Compound 32

Compound 32 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.42 (s, 1H), 8.62 (s, 1H), 8.44-8.42 (d, 1H), 8.35-8.33 (d, 1H), 8.04 (s, 1H) ), 7.90-7.83 (m, 4H), 7.75-7.71 (m, 2H), 7.11-7.10 (d, 1H), 7.47 (m, 1H), 5.20 (s, 2H); LCMS (ESI): m/z 391.0 (M+H).

Example 33

Synthesis of compound 33

Compound 33 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.44-8.42 (d, 1H), 7.90-7.88 (d, 1H), 7.79-7.77 (m, 1H), 7.67-7.66 (m, 2H), 7.59 -7.57 (d, 1H), 7.51-7.50 (d, 1H), 7.24-7.21 (m, 2H), 5.03 (s, 2H); LCMS (ESI): m/z 407.9 (M+H).

Example 34

Synthesis of compound 34

Compound 34 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.46-8.44 (d, 1H), 8.05-8.03 (d, 1H), 7.83-7.81 (m, 1H), 7.73-7.69 (m, 2H), 7.40 -7.37 (d, 2H), 7.16-7.13 (m, 1H), 7.06-7.05 (d, 1H), 5.16 (s, 2H), 2.32 (s, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 35

Synthesis of compound 35

Compound 35 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.46-8.45 (d, 1H), 8.05-8.03 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.68 (m, 2H), 7.45 -7.42 (d, 1H), 7.28 (s, 1H), 7.13-7.04 (d, 2H), 5.15 (s, 2H), 2.32 (s, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 36

Synthesis of compound 36

Compound 36 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.51 (d, J =5.77 Hz, 1H), 8.09 (d, J =7.78 Hz, 1H), 7.92-7.84 (m, 1H), 7.79-7.66 ( m, 4H), 7.41 (d, J =8.53 Hz, 1H), 7.12 (d, J =5.77 Hz, 1H), 5.20 (s, 2H); LCMS (ESI): m/z 458.0 (M+H).

Example 37

Synthesis of compound 37

Compound 37 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.51-8.49 (d, 1H), 8.08-8.06 (d, 1H), 7.88-7.86 (d, 1H), 7.76-7.71 (m, 2H), 7.49 -7.47 (d, 1H) 7.27-7.24 (d, 1H), 7.14-7.09 (m, 3H), 5.18 (s, 2H); LCMS (ESI): m/z : 358.0 (M+H).

Example 38

Synthesis of compound 38

Compound 38 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 5.19 (s, 2H), 7.10 (d, 1H), 7.45-7.58 (m, 3H), 7.67-7.79 (m, 2H), 7.81-7.90 (m , 1H), 8.07 (d, 1H), 8.52 (d, 1H); LCMS (ESI): m/z 409.9 (M+H).

Example 39

Synthesis of compound 39

Compound 39 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.49 (d, 1H), 8.09 (d, 1H), 7.91-7.83 (m, 1H), 7.80-7.68 (m, 2H), 7.35 (t, 1H) ), 7.09 (d, 1H), 6.91–6.80 (m, 3H), 5.20 (s, 2H), 3.78 (s, 3H); LCMS (ESI): m/z 370.0 (M+H).

Example 40

Synthesis of compound 40

Compound 40 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.53 (d, 1H), 8.08 (d, 1H), 7.96 (d, 2H), 7.90-7.83 (m, 1H), 7.80-7.68 (m, 2H) ), 7.14 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 365.0 (M+H).

Example 41

Synthesis of compound 41

Compound 41 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.50 (d, 1H), 8.09 (d, 1H), 7.82-7.91 (m, 1H), 7.69-7.80 (m, 2H), 7.64 (d, 2H) ), 7.28 (d, 2H), 7.10 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 419.9 (M+H).

Example 42

Synthesis of compound 42

Compound 42 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.49 (d, 1H), 8.08 (d, 1H), 7.90-7.82 (m, 1H), 7.79-7.67 (m, 2H), 7.38-7.23 (m , 4H), 7.09 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 358.0 (M+H).

Example 43

Synthesis of compound 43

Compound 43 was synthesized in a similar manner to compound 15 . ^1H _ NMR (DMSO- d ₆ , 400 MHz) δ 8.50 (d, J =5.27 Hz, 1H), 8.08 (d, J =7.78 Hz, 1H), 7.91-7.82 (m, 1H), 7.79-7.63 (m, 2H), 7.43 (t, J =7.53 Hz, 2H), 7.30 (d, J =8.53 Hz, 2H), 7.16 (t, J =7.28 Hz, 1H), 7.12-7.01 (m, 5H), 5.20 ( s, 2H); LCMS (ESI): m/z 432.0 (M+H).

Example 44

Synthesis of Compound 44

Compound 44 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.46 (d, J =5.27 Hz, 1H), 8.08 (d, J =7.78 Hz, 1H), 7.91-7.82 (m, 1H), 7.80-7.60 ( m, 2H), 7.19 (d, J =8.53 Hz, 2H), 7.07 (d, J =5.52 Hz, 1H), 6.99 (d, J =8.53 Hz, 2H), 5.19 (s, 2H), 3.79 ( s, 3H); LCMS (ESI): m/z 370.0 (M+H).

Example 45

Synthesis of Compound 45

Compound 45 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.45-8.44 (d, 1H), 8.08-8.06 (d, 1H), 7.84 (m, 1H), 7.76-7.71 (m, 2H), 7.49-7.47 (m, 2H), 7.43 (m, 2H), 7.41-7.39 (m, 1H), 7.19-7.17 (m, 2H), 7.07-7.05 (m, 3H), 5.18 (s, 2H), 5.13 (s) , 2H); LCMS (ESI): m/z 446.1 (M+H).

Example 46

Synthesis of compound 46

Compound 46 was synthesized in a similar manner to compound 15 . ^1H NMR (DMSO- d ₆ , 400 MHz) δ 8.51 (d , J =5.52 Hz, 1H), 8.09 (d, J =7.78 Hz, 1H), 7.93-7.83 (m, 1H), 7.80-7.61 (m, 2H), 7.22 (d, J =12.80 Hz, 2H), 7.13-6.95 (m, 2H), 5.21 (s, 2H), 2.35 (s, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 47

Synthesis of compound 47

Compound 47 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.50 (d, J =5.73 Hz, 1H), 8.06 (d, J =7.94 Hz, 1H), 7.91-7.79 (m, 3H), 7.76-7.67 ( m, 2H), 7.51 (d, J =8.82 Hz, 2H), 7.11 (d, J =5.73 Hz, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 408.0 (M+H).

Example 48

Synthesis of compound 48

Compound 48 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.30 (s, 1H), 8.50 (d, J =5.73 Hz, 1H), 8.25 (s, 1H), 8.06 (d, J =7.50 Hz, 1H) , 7.92 (d, J =8.82 Hz, 2H), 7.87-7.81 (m, 1H), 7.76-7.63 (m, 2H), 7.47 (d, J =9.26 Hz, 2H), 7.09 (d, J =5.73 Hz, 1H), 5.18 (s, 2H); LCMS (ESI): m/z 407.0 (M+H).

Example 49

Synthesis of compound 49

Compound 49 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.50-8.48 (d, 1H), 8.09-8.07 (d, 1H), 7.86-7.84 (d, 1H), 7.76 - 7.70 (m, 2H), 7.47 -7.40 (m, 4H), 7.10-7.09 (m, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 424.0 (M+H).

Example 50

Synthesis of Compound 50

Compound 50 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.55-8.53 (d, 1H), 8.37 (m, 2H), 8.08-8.06 (d, 1H), 7.88-7.84 (t, 1H), 7.76-7.69 (m, 3H), 7.11-7.09 (m, 1H), 5.19 (s, 2H), 3.89 (s, 3H); LCMS (ESI): m/z 371.0 (M+H).

Example 51

Synthesis of Compound 51

Compound 51 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.59-8.57 (m, 2H), 8.54-8.52 (m, 1H), 8.12 (s, 1H), 8.08-8.06 (d, 1H), 7.86-7.84 (m, 1H), 7.76-7.71 (m, 2H), 7.12-7.10 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 375.0 (M+H).

Example 52

Synthesis of Compound 52

Compound 52 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.65-8.62 (m, 2H), 8.54-8.52 (d, 1H), 8.23 (s, 1H), 8.08-8.06 (d, 1H), 7.86-7.84 (m, 1H), 7.76-7.71 (m, 2H), 7.11-7.10 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 419.0 (M+H).

Example 53

Synthesis of compound 53

Compound 53 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.72 (s, 1H); 8.50 (d, 1H), 8.03 (d, 1H), 7.87-7.80 (m, 1H), 7.77-7.66 (m, 3H), 7.10 (d, 1H), 5.18 (s, 2H), 2.66 (s, 3H), 2.28 (s, 3H); LCMS (ESI): m/z 369.1 (M+H).

Example 54

Synthesis of Compound 54

Compound 54 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.53-8.51 (d, 1H), 8.46-8.45 (d, 1H), 8.08-8.06 (d, 1H), 7.91-7.90 (d, 1H), 7.86 (m, 1H), 7.76-7.71 (m, 2H), 7.64-7.62 (d, 1H), 7.12-7.10 (d, 1H), 5.18 (s, 2H); LCMS (ESI): m/z 375.0 (M+H).

Example 55

Synthesis of Compound 55

Compound 55 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.83 (d, 1H), 8.56 (d, 1H), 8.23-8.17 (m, 1H), 8.14-8.05 (m, 2H), 7.91-7.83 (m , 1H), 7.79-7.68 (m, 2H), 7.15 (d, 1H), 5.19 (s, 2H); LCMS (ESI): m/z 366.0 (M+H).

Example 56

Synthesis of compound 56

Compound 56 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.48 (d, 1H), 8.07 (d, 1H), 7.90-7.81 (m, 1H), 7.79-7.67 (m, 2H), 7.48-7.22 (m , 4H), 7.10 (d, 1H), 5.20 (bs, 2H); LCMS (ESI): m/z 358.0 (M+H).

Example 57

Synthesis of compound 57

Compound 57 was synthesized in a similar manner to compound 15 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.48 (d, J =5.73 Hz, 1H), 8.06 (d, J =7.94 Hz, 1H), 7.91-7.81 (m, 1H), 7.80-7.67 ( m, 3H), 7.60 (d, J =9.26 Hz, 1H), 7.52-7.43 (m, 1H), 7.15-7.06 (m, 1H), 5.27-5.14 (m, 2H); LCMS (ESI): m/z 458.0 (M+H).

Example 58

Synthesis of compound 58

A mixture of 3 (30 mg, 0.11 mmol) and cyclobutanol (230 mg, 3.2 mmol) in HCl/dioxane (4M, 1.5 mL) was heated to 100 °C for 16 h. Upon completion the reaction mixture was concentrated under reduced pressure. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 58 (1.6 mg, 5%) as a white solid. ^1H NMR (DMSO- d ₆ , 400MHz) δ ppm 8.45 (d, J =5.73 Hz, 1H), 8.02 (d, J =7.94 Hz , 1H), 7.86-7.79 (m, 1H), 7.76-7.65 (m, 2H), 6.89 (d, J =5.73 Hz, 1H), 5.16 (s, 2H), 5.14-5.05 (m, 1H), 2.15-2.01 (m, 2H), 1.78 (q, J =10.14 Hz, 1H), 1.70-1.55 (m, 1H); LCMS (ESI): m/z 318 (M+H).

Example 59

Synthesis of compound 59

Compound 59 was synthesized in a similar manner to compound 58 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.47-8.46 (d, 1H), 8.05-8.03 (d, 1H), 7.86-7.82 (m, 1H), 7.75-7.68 (m, 2H), 6.88 -6.87 (d, 1H), 5.17 (s, 2H), 4.99-4.95 (m, 1H), 2.01-1.90 (m, 2H), 1.75-1.73 (m, 2H), 1.54-1.29 (m, 6H) ; LCMS (ESI): m/z 346 (M+H).

Example 60

Synthesis of compound 60

Compound 60 was synthesized in a similar manner to compound 58 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.27 (d, J =5.73 Hz, 1H), 7.87 (d, J =7.94 Hz, 1H), 7.82-7.74 (m, 1H), 7.72-7.62 ( m, 2H), 6.47 (d, J =6.17 Hz, 1H), 5.62-5.50 (m, 1H), 5.19-5.05 (m, 2H), 2.20-2.05 (m, 2H), 1.90-1.74 (m, 4H), 1.73-1.57 (m, 2H); LCMS (ESI): m/z 332.0 (M+H).

Example 61

Synthesis of compound 61

Compound 61 was synthesized in a similar manner to compound 58 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.17-8.15 (d, 1H), 7.96-7.94 (d, 1H), 7.88-7.84 (m, 1H), 7.74-7.71 (m, 2H), 6.97 ( bs, 1H), 5.27 (s, 2H), 4.47-4.48 (m, 1H), 4.32-4.29 (d, 1H), 4.21-4.16 (m, 1H), 3.89-3.86 (d, 1H), 3.56- 3.53 (d, 1H), 3.40 (s, 3H); LCMS (ESI): m/z 333.0 (M+H).

Example 62

Synthesis of compound 62

Compound 62 was synthesized in a similar manner to compound 58 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.28-8.26 (d, 1H), 8.04-8.02 (d, 1H), 7.86-7.82 (t, 1H), 7.74-7.68 (m, 2H), 6.63 -6.61 (d, 1H), 5.22 (s, 2H), 4.20-4.17 (m, 2H), 3.81-3.77 (m, 1H), 3.51-3.46 (t, 2H), 1.83-1.80 (m, 2H) , 1.45–1.39 (m, 2H); LCMS (ESI): m/z 347.0 (M+H).

Example 63

Synthesis of compound 63

Compound 63 was synthesized in a similar manner to compound 58 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.51-8.50 (d, 1H), 8.00-7.98 (d, 1H), 7.86-7.81 (m, 1H), 7.75-7.69 (m, 2H), 7.00 -6.99 (d, 1H), 5.61-5.55 (m, 1H), 5.19 (s, 2H), 4.08 (m, 1H), 3.67-3.53 (m, 2H), 3.28-3.18 (m, 1H), 2.86 (s, 3H), 2.70-2.66 (m, 1H), 2.31-2.22 (m, 1H); LCMS (ESI): m/z 347.1 (M+H).

Example 64

Synthesis of Compound 64

Compound 64 was synthesized in a similar manner to compound 58 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.47-8.45 (d, 1H), 8.03-8.01 (d, 1H), 7.82-7.80 (d, 1H), 7.72-7.66 (m, 2H), 6.88 -6.87 (d, 1H), 5.16 (s, 1H), 5.14-5.10 (m, 1H), 5.0 (s, 2H), 3.88-3.84 (m, 2H), 3.50-3.44 (m, 2H), 2.07 -2.05 (m, 2H), 1.70-1.64 (m, 2H); LCMS (ESI): m/z 348.0 (M+H).

Example 65

Synthesis of Compound 65

Compound 65 was synthesized in a similar manner to compound 58 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.94-7.92 (d, 1H), 7.86-7.82 (t, 1H), 7.73-7.69 (m, 2H), 7.10-7.09 (d, 1H), 5.69 ( s, 1H), 5.19 (s, 1H), 4.14-4.10 (m, 1H), 4.02-3.99 (m, 2H), 3.92-3.91 (m, 1H), 2.45-2.35 (m, 2H), 2.26- 2.22 (m, 1H); LCMS (ESI): m/z 334.0 (M+H).

Example 66

Synthesis of compound 66

Compound 66 was synthesized in a similar manner to compound 58 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.26-8.22 (d, 1H), 7.99-7.97 (d, 1H), 7.82-7.80 (d, 1H), 7.73-7.66 (m, 2H), 6.48 -6.46 (d, 1H), 5.11 (s, 1H), 4.75 (s, 1H), 3.97-3.92 (m, 1H), 3.88-3.85 (m, 2H), 3.70-3.66 (m, 1H), 1.89 (m, 1H), 1.72 (m, 2H), 1.52 (m, 1H); LCMS (ESI): m/z 389.1 (M+H).

Example 67

Synthesis of compound 67

Compound 67 was synthesized in a similar manner to compound 58 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.42 (bs, 1 H), 7.93 (d, J =7.94 Hz, 1H), 7.86-7.79 (m, 1H), 7.75-7.61 (m, 2H), 7.09 (d, J =6.17 Hz, 1H) 5.28-5.12 (m, 2H), 4.56 (q, J =7.06 Hz, 2H), 1.52-1.41 (m, 3H); LCMS (ESI): m/z 292.0 (M+H).

Example 68

Synthesis of compound 68

Compound 68 was synthesized in a similar manner to compound 58 . 1H NMR (DMSO- d ₆ , 400 MHz) δ 8.49 (d, J=5.77 Hz, 1H), 8.06 (d, J=7.78 Hz, 1H), 7.91-7.81 (m, 1H), 7.78-7.66 (m , 2H), 6.95 (d, J=5.77 Hz, 1H), 5.21 (s, 2H), 4.33 (d, J=7.03 Hz, 2H), 2.78 (q, J=7.40 Hz, 1H), 2.15-2.01 (m, 2 H), 1.96-1.76 (m, 4 H); LCMS (ESI): m/z 360.1 (M+H).

Example 69

Synthesis of compound 69

Compound 69 was synthesized in a similar manner to compound 58 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.40 (d, J =6.17 Hz, 1H), 7.93 (d, J =7.94 Hz, 1H), 7.78-7.86 (m, 1H), 7.74-7.65 (m , 2H), 7.13-7.02 (m, 1H), 5.20 (s, 2H), 4.36-4.27 (m, 2H), 1.96-1.64 (m, 6H), 1.40-1.05 (m, 5H); LCMS (ESI): m/z 332.1 (M+H).

Example 70

Synthesis of Compound 70

A mixture of 3 (30 mg, 0.11 mmol), benzyl alcohol (17 mg, 0.16 mmol), potassium carbonate (29 mg, 0.21 mmol), and cesium fluoride (33 mg, 0.21 mmol) in DMF (2 mL) was stirred in an inert atmosphere. It stirred at 65 degreeC for 10 hours under. Upon completion the reaction mixture was filtered and concentrated under reduced pressure. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 70 (2 mg, 5%). ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.51-8.49 (d, 1H), 7.84-7.83 (d, 1H), 7.75-7.70 (m, 2H), 7.50-7.49 (d, 2H), 7.39- 7.35 (m, 2H), 7.33–6.98 (m, 1H), 5.43 (s, 2H), 5.20 (s, 2H); LCMS (ESI): m/z 354.0 (M+H).

Example 71

Synthesis of Compound 71

Compound 71 was synthesized in a similar manner to compound 70 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.94-9.91 (d, 2H), 9.08-9.04 (d, 1H), 8.88-8.06 (d, 1H), 8.40-8.38 (d, 1H), 8.17 -8.15 (d, 1H), 7.93-7.91 (d, 1H), 7.82-7.70 (d, 1H), 7.76-7.64 (d, 1H), 6.16-6.13 (t, 1H), 5.48 (s, 2H) , 4.90–4.89 (d, 2H); LCMS (ESI): m/z 355.0 (M+H).

Example 72

Synthesis of Compound 72

Compound 72 was synthesized in a similar manner to compound 70 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.85-8.83 (d, 2H), 8.63-8.60 (d, 1H), 8.61-8.50 (d, 1H), 8.24-8.03 (m, 1H), 7.89- 7.87 (d, 1H), 7.71-7.69 (m, 1H), 7.03-7.01 (d, 1H), 5.87 (s, 2H), 5.17-5.11 (d, 2H); LCMS (ESI): m/z 355.0 (M+H).

Example 73

Synthesis of Compound 73

Compound 73 was synthesized in a similar manner to compound 70 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.83-8.82 (d, 2H), 8.48-8.47 (d, 1H), 8.18-8.16 (d, 2H), 7.88-7.79 (m, 2H), 7.70 -7.68 (d, 2H), 7.00-6.99 (d, 1H), 5.82 (s, 2H), 5.09 (s, 2H); LCMS (ESI): m/z 355.0 (M+H).

Example 74

Synthesis of Compound 74

A mixture of 3 (30 mg, 0.11 mmol) and 1-methylpiperidin-4-ol (182 mg, 1.59 mmol) in DMSO (1.0 mL) was mixed at 50 °C for 2 h. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 74 (12 mg, 32%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.51-8.50 (d, 1H), 7.95-7.92 (m, 1H), 7.86-7.84 (m, 1H), 7.75-7.66 (m, 2H), 7.11- 7.06 (m, 1H), 5.22 (s, 2H), 4.77-4.74 (m, 1H), 3.69-3.66 (d, 1H), 3.51-3.48 (d, 1H), 3.38-3.34 (m, 2H), 2.95 (s, 3H), 2.65-2.63 (d, 1H), 2.50-2.46 (d, 1H), 2.28-2.21 (m, 1H), 2.11-2.04 (m, 1H); LCMS (ESI): m/z 361.0 (M+H).

Example 75

Synthesis of Compound 75

Step 1.

A mixture of 3 (200 mg, 0.71 mmol), methyl-2-hydroxyacetate (192 mg, 2.13 mmol), CsF (216 mg, 1.42 mmol) and potassium carbonate (196 mg, 1.42 mmol) in DMF (3 mL) was stirred at 120° C. for 4 h under an inert atmosphere. The resulting mixture was filtered and purified by pre-HPLC (0.075% TFA/CH ₃ CN/H ₂ O system) to give 7 (60 mg, 25%).

Step 2.

To a solution of 7 (30 mg, 0.09 mmol) in MeOH (2 mL) was added NH ₃ .H ₂ O (9.4 mg, 0.27 mmol). The mixture was stirred at 60 °C for 2 h. Upon completion the reaction mixture was concentrated under reduced pressure and purification by pre-HPLC (0.04%HCl/CH ₃ CN/H ₂ O system) gave compound 75 (2.5 mg, 8.5%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.48 (d, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.76-7.72 (t, 2H), 7.51 (s, 1H), 7.20 (d, 1H), 6.99 (d, 1H), 5.19 (s, 2H), 4.75 (s, 2H); LCMS (ESI): m/z 321.0 (M+H).

Example 76

Synthesis of Compound 76

Compound 76 was synthesized in a similar manner to compound 75 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 10.23 (s, 1H), 8.50-8.48 (d, 1H), 8.06-8.04 (d, 1H), 7.84-7.82 (t, 1H), 7.70-7.65 (dd, 2H), 7.62-7.60 (d, 2H), 7.33-7.29 (t, 2H), 7.07-7.05 (t, 1H), 7.05-6.99 (d, 1H), 5.16 (s, 2H), 4.98 (s, 2H); LCMS (ESI): m/z 397 (M+H).

Example 77

Synthesis of compound 77

Step 1.

To a solution of 6-methyl-2,4-dichloropyrimidine (120 mg, 0.74 mmol) and pyridin-3-ol (70 mg, 0.74 mmol) in anhydrous DMF (4 mL) was added potassium carbonate (204 mg, 1.47 mmol). ) was added and the resulting mixture was heated to 50° C. for 2 hours. Upon completion the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were washed with water (150 mL), saturated brine (80 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave 8 (150 mg), which was used in the next step without further purification.

Step 2.

To a solution of 8 (150 mg, 0.54 mmol) and 1 (92 mg, 0.54 mmol) in anhydrous DMF (4 mL) was added cesium carbonate (353 mg, 1.08 mmol) and the resulting mixture was stirred at 40° C. for 2 h. Upon completion the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 77 (3.9 mg, 9.0%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.78 (d, 1H), 8.61 (d, 1H), 8.10-8.03 (m, 2H), 7.84 (d, 1H), 7.76-7.71 (m, 3H) , 6.99 (s, 1H), 5.14 (s, 2H), 2.40 (s, 3H); LCMS (ESI): m/z 355.0 (M+H).

Example 78

Synthesis of compound 78

Compound 78 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.14 (s, 1H), 8.80 (s, 1H), 8.63-8.61 (d, 1H), 8.17-8.15 (m, 1H), 7.89-7.80 (m , 2H), 7.70–7.67 (m, 2H), 7.43 (s, 1H), 5.15 (s, 2H); LCMS (ESI): m/z 409.0 (M+H).

Example 79 and 80

Synthesis of compounds 79 and 80

Compounds 79 and 80 were synthesized in a similar manner to compound 77. Separation of the isomers (~1:1 ratio) was achieved by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system). compound 79 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.19 (s, 1H), 8.76-8.75 (d, 1H), 8.63-8.61 (d, 1H), 8.15-8.13 (m, 1H), 7.85-7.78 ( m, 2H), 7.69-7.65 (m, 2H), 6.35 (s, 1H), 5.01 (s, 2H), 4.01 (s, 3H); LCMS (ESI): m/z 371.0 (M+H). compound 80. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 9.20-9.19 (d, 1H), 8.75-8.73 (d, 1H), 8.58-8.57 (d, 1H), 8.14-8.11 (m, 1H), 7.83-7.77 (m, 2H), 7.68-7.64 (m, 2H), 6.28 (s, 1H), 5.11 (s, 2H), 4.10 (s, 3H); LCMS (ESI): m/z 371.0 (M+H).

Example 81

Synthesis of Compound 81

Compound 81 was synthesized in a similar manner to compound 77 . ^1H NMR (DMSO- d ₆ , 400 MHz) δ 8.61 ( s , 2H), 8.10-8.08 (d, 1H), 7.95-7.93 (d, 1H), 7.87-7.85 (d, 1H), 7.75- 7.71 (m, 2H), 7.65 (m, 2H), 5.24 (s, 2H); LCMS (ESI): m/z 366 (M+H).

Example 82

Synthesis of Compound 82

Compound 82 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.74 (bs, 1H); 8.58 (d, 1H), 8.09-7.98 (m, 2H), 7.89-7.82 (m, 1H), 7.72 (dd, 3H), 6.97 (s, 1H), 5.16 (s, 2H), 2.68 (q, 2H), 1.18 (t, 3H); LCMS (ESI): m/z 369.0 (M+H).

Example 83

Synthesis of Compound 83

Compound 83 was synthesized in a similar manner to compound 77 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 9.19 (d, J =1.76 Hz, 1H), 8.78 (d, J =5.73 Hz, 1H), 8.67 (dd, J =8.60, 1.54 Hz, 1H) , 8.20 (dd, J =8.82, 5.73 Hz, 1H), 7.91-7.78 (m, 2H), 7.68 (dt, J =7.61, 3.47 Hz, 2H), 7.00 (s, 1H), 5.16-5.04 (m , 2H), 2.21-2.12 (m, 1H), 1.18-1.11 (m, 4H); LCMS (ESI): m/z 381.0 (M+H).

Example 84

Synthesis of Compound 84

Compound 84 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.92 (bs, 1H); 8.69 (d, 1H), 8.28 (d, 1H), 8.04 (d, 1H), 7.85 (t, 2H), 7.76-7.66 (m, 2H), 6.96 (s, 1H), 5.18 (s, 2H) , 2.96 (m, 1H), 1.20 (d, 6H); LCMS (ESI): m/z 383.1 (M+H).

Example 85

Synthesis of Compound 85

Compound 85 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.96 (s, 1H), 8.72-8.71 (d, 1H), 8.31 (s, 1H), 8.06-8.02 (m, 3H), 7.88-7.84 (t , 2H), 7.75-7.72 (m, 2H), 7.42 (s, 1H), 7.10-7.08 (d, 2H), 5.29 (s, 2H), 3.84 (s, 3H); LCMS (ESI): m/z 447.1 (M+H).

Example 86 and 87

Synthesis of compounds 86 and 87

Compounds 86 and 87 were synthesized in a similar manner to compound 77 . Separation of the isomers was achieved by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system). compound 86 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.07-8.05 (d, 1H), 7.84-7.82 (d, 1H), 7.74-7.70 (m, 2H), 7.50-7.48 (d, 2H), 7.32- 7.30 (d, 2H), 6.96 (s, 1H), 5.14 (s, 2H), 3.37 (s, 3H); LCMS (ESI): m/z 388.0 (M+H). compound 87 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 7.97-7.95 (d, 1H), 7.79-7.77 (d, 1H), 7.73-7.71 (d, 1H), 7.67-7.65 (d, 1H), 7.53 -7.51 (d, 2H), 7.39-7.37 (d, 2H), 6.63 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 88

Synthesis of compound 88

Compound 88 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.98-8.97 (d, 1H), 8.74-8.72 (t, 2H), 8.35-8.33 (d, 1H), 8.09-8.07 (d, 2H), 7.91 -7.84 (m, 2H), 7.75-7.71 (t, 2H), 7.60 (s, 1H), 5.21 (s, 1H), 2.82-2.80 (d, 3H); LCMS (ESI): m/z 398.0 (M+H).

Example 89

Synthesis of compound 89

Compound 89 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.63 (s, 1H), 8.09-8.07 (d, 1H), 7.85-7.83 (d, 1H), 7.76-7.71 (m, 2H), 7.58 (s , 1H), 7.52-7.50 (d, 2H), 7.41-7.39 (d, 2H), 5.16 (s, 1H), 2.82-2.81 (d, 3H); LCMS (ESI): m/z 431.0 (M+H).

Example 90

Synthesis of compound 90

Compound 90 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.56 (s, 1H), 8.50-8.48 (d, 2H), 7.80-7.78 (d, 1H), 7.64-7.62 (m, 2H), 7.52-7.51 (d, 1H), 7.41-7.39 (d, 1H), 7.08-7.07 (d, 1H), 5.07 (s, 2H), 3.88 (s, 3H); LCMS (ESI): m/z 371.0 (M+H).

Example 91

Synthesis of compound 91

Compound 91 was synthesized in a similar manner to compound 77 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.98 (d, 1H), 7.93-7.85 (m, 1H), 7.79-7.71 (m, 2H), 7.13 (s, 1H), 5.40 (s, 1H) , 5.28 (s, 2H), 3.42–3.33 (m, 2H), 3.03–2.91 (m, 2H), 2.62 (s, 3H); LCMS (ESI): m/z 368.1 (M+H).

Example 92

Synthesis of Compound 92

Compound 92 was synthesized in a similar manner to compound 77 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.89 (d, 1H), 7.81-7.75 (m, 1H), 7.71-7.64 (m, 2H), 6.46 (s, 1H), 5.26-5.16 (m, 1H), 5.12 (s, 2H), 3.29-3.21 (m, 2H), 2.81-2.68 (m, 2H), 2.42 (s, 3H); LCMS (ESI): m/z 368.0 (M+H).

Example 93

Synthesis of compound 93

Compound 93 was synthesized in a similar manner to compound 77 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.89 (d, 1H), 7.82-7.76 (m, 1H), 7.72-7.64 (m, 2H), 6.26 (s, 1H), 5.14 (s, 1H) , 5.06 (s, 2H), 4.01–3.90 (m, 3H), 3.27–3.17 (m, 2H), 2.83–2.70 (m, 2H); LCMS (ESI): m/z 384.0 (M+H).

Example 94

Synthesis of compound 94

Compound 94 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d _6, 400 MHz) δ 8.39-8.38 (d, 1H), 7.92-7.90 (d, 1H), 7.83-7.79 (t, 1H), 7.72-7.69 (m, 2H), 6.62 -6.61 (d, 1H), 6.41-6.20 (m, 1H), 5.15 (s, 2H), 3.28-3.21 (m, 2H), 2.84-2.77 (m, 2H); LCMS (ESI): m/z 354.0 (M+H).

Example 95

Synthesis of Compound 95

Compound 95 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ 400 MHz) δ 8.03 (d, J =7.78 Hz, 1H), 7.90-7.80 (m, 1H), 7.77-7.66 (m, 2H), 7.50 (d, J =8.78 Hz , 2H), 7.41-7.30 (m, 2H), 6.41-6.20 (m, 1H), 5.10 (s, 2H), 3.84 (s, 3H); LCMS (ESI): m/z 404.0 (M+H).

Example 96

Synthesis of compound 96

Compound 96 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 7.97 (d, J =7.78 Hz, 1H), 7.87-7.78 (m, 1H), 7.76-7.71 (m, 1H), 3.99 (s, 3H), 7.70-7.62 (m, 1H), 7.52 (d, J =8.78 Hz, 2H), 7.36 (d, J =8.78 Hz, 2H), 6.04 (s, 1H), 5.05 (s, 2H); LCMS (ESI): m/z 404.0 (M+H).

Example 97

Synthesis of Compound 97

Compound 97 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.10 (d, 1H), 7.90-7.84 (m, 1H), 7.77-7.69 (m, 2H), 7.53 (d, 2H), 7.40 (d, 2H) ), 7.34 (s, 1H), 5.26 (s, 2H); LCMS (ESI): m/z 442.1 (M+H).

Example 98

Synthesis of compound 98

Compound 98 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.09 (d, 1H), 7.89-7.84 (m, 1H), 7.76-7.71 (m, 2H), 7.50-7.45 (m, 2H), 7.35-7.30 (m, 4H), 5.26 (s, 2H); LCMS (ESI): m/z 408.0 (M+H).

Example 99

Synthesis of compound 99

Compound 99 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.03 (d, J =7.78 Hz, 1H), 7.89-7.80 (m, 1H), 7.75-7.57 (m, 2H), 7.37 (dd, J =8.91 , 4.64 Hz, 2H), 7.32–7.21 (m, 2H), 5.09 (s, 2H), 6.31 (s, 1H), 3.90–3.73 (m, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 100

Synthesis of Compound 100

Compound 100 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.02 (d, 1H), 7.85-7.80 (m, 1H), 7.70 (d, 2H), 7.47-7.42 (m, 2H), 7.33-7.25 (m , 3H), 6.30 (s, 1H), 5.08 (s, 2H), 3.81 (s, 3H); LCMS (ESI): m/z 370.0 (M+H).

Example 101

Synthesis of Compound 101

Compound 101 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 7.97 (d, J =7.78 Hz, 1H), 7.86-7.77 (m, 1H), 7.75-7.71 (m, 1H), 7.70-7.62 (m, 1H) ), 7.40-7.25 (m, 4H), 5.95 (s, 1H), 5.11-4.97 (m, 2H), 3.98 (s, 3H); LCMS (ESI): m/z 388.0 (M+H).

Example 102

Synthesis of Compound 102

Compound 102 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO -d ₆ , 400 MHz) δ 7.96 (d, 1H), 7.82-7.76 (m, 1H), 7.73-7.64 (m, 2H), 7.50-7.45 (m, 2H), 7.33-7.28 (m, 3H), 5.86 (s, 1H), 5.05 (s, 2H), 3.96 (s, 3H); LCMS (ESI): m/z 370.1 (M+H).

Example 103

Synthesis of Compound 103

Compound 103 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO -d ₆ , 400 MHz) δ 8.09 (d, 1H), 7.89-7.84 (m, 1H), 7.76-7.70 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 2H), 7.30–7.27 (m, 1H), 5.25 (s, 2H); LCMS (ESI): m/z 426.0 (M+H).

Example 104

Synthesis of Compound 104

Compound 104 was synthesized in a similar manner to compound 77 . ^1H NMR (DMSO -d ₆ , 400 MHz) δ 7.95 (d, 1H), 7.81-7.76 (m, 1H), 7.73-7.74 (m, 1H), 7.68-7.63 (m, 1H), 7.40-7.35 (m, 2H), 7.33-7.27 (m, 2H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H); LCMS (ESI): m/z 372.1 (M+H).

Example 105

Synthesis of Compound 105

Compound 105 was synthesized in a similar manner to compound 77 . ^1H NMR (DMSO- d ₆ , 400MHz) δ 7.95 ( d , 1H), 7.82-7.76 (m, 1H), 7.73-7.64 (m, 2H), 7.51-7.46 (m, 2H), 7.35-7.30 (m, 3 H), 6.51 (s, 1H), 5.05 (s, 2H), 2.41 (s, 3H); LCMS (ESI): m/z 354.0 (M+H).

Example 106

Synthesis of Compound 106

Compound 106 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.05 (d, 1H), 7.87-7.81 (m, 1H), 7.75-7.68 (m, 2H), 7.33-7.21 (m, 4H), 6.94 (s, 1H), 5.13 (s, 2H), 2.36 (s, 3H); LCMS (ESI): m/z 372.1 (M+H).

Example 107

Synthesis of Compound 107

Compound 107 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.05 (d, 1H), 7.87-7.81 (m, 1H), 7.75-7.67 (m, 2H), 7.47-7.41 (m, 2H), 7.28-7.23 (m, 3H), 6.95 (s, 1H), 5.14 (s, 2H), 2.36 (s, 3H); LCMS (ESI): m/z 354.0 (M+H).

Example 108

Synthesis of Compound 108

Compound 108 was synthesized in a similar manner to compound 77 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.53 (s, 1H), 8.45 (d, 1H), 7.89 (d, 1H), 7.76 (t, 2H), 7.70-7.59 (m, 2H), 7.47 (dd, 1H), 6.12 (s, 1H), 4.92 (s, 2H), 3.67 (s, 4H), 2.33 (s, 4H), 2.26 (s, 3H); LCMS (ESI): m/z 439.1 (M+H).

Example 109

Synthesis of Compound 109

To a solution of 3 (120 mg, 0.43 mmol) and 1-methylsulfonylazetidin-3-ol (77 mg, 0.51 mmol) in THF (2 mL) was added t-BuOK (96 mg, 0.85 mmol) at 0 °C. added The resulting mixture was stirred at 0 °C for 2 h. Upon completion the reaction mixture was quenched by the addition of NH ₄ Cl (5 mL) at 0 °C and then extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 109 (13 mg, 7%) as a white solid. ^1H NMR (DMSO- d ₆ , 400MHz) δ 8.53-8.46 (m, 1H), 8.05 (d, J=7.94 Hz, 1H), 7.91-7.82 (m, 1H), 7.77- 7.52 (m , 2H) , 7.03-6.86 (m, 1H), 5.40-5.25 (m, 1H), 5.23 - 5.13 (m, 2 H), 4.32 (dd, J=9.48, 6.84 Hz, 2H), 4.09-3.96 (m, 2H) ), 3.06 (s, 3H); LCMS (ESI): m/z 397.0 (M+H).

Example 110

Synthesis of Compound 110

Compound 110 was synthesized in a similar manner to compound 109 . 1H NMR (methanol- d _4, 400MHz) δ 8.45 (d, J =5.77 Hz, 1H), 7.94 (d, J =7.78 Hz, 1H), 7.88-7.81 (m, 1H), 7.75-7.66 (m, 2H), 7.06 (d, J =5.77 Hz, 1H), 5.47 (bs, 1H), 5.17 (s, 2H), 4.75 (t, J =8.28 Hz, 1H), 4.55-4.45 (m, 1H), 4.33 (d, J =7.53 Hz, 1H), 4.07 (d, J =10.54 Hz, 1H), 1.94 (s, 3H); LCMS (ESI): m/z 361.0 (M+H).

Example 111

Synthesis of Compound 111

Compound 111 was synthesized in a similar manner to compound 109 . ¹ H NMR: (methanol- d _4, 400 MHz) δ 8.33 (d, J =5.73 Hz, 1H), 7.87 (d, J =7.94 Hz, 1H), 7.82-7.75 (m, 1H), 7.71-7.62 ( m, 2H), 6.54 (d, J =5.73 Hz, 1H), 5.43 (dt, J =8.05, 4.13 Hz, 1H), 5.13 (s, 2H), 4.08-3.97 (m, 1H), 3.83 (d , J =13.67 Hz, 1H), 3.58-3.39 (m, 2H), 2.30-2.05 (m, 5H), 1.95-1.62 (m, 1H); LCMS (ESI): m/z 389.1 (M+H).

Example 112

Synthesis of Compound 112

Compound 112 was synthesized in a similar manner to compound 109 . ¹ H NMR: (methanol- d _4, 400 MHz) δ 8.42 (t, J =5.29 Hz, 1H), 8.02-7.79 (m, 2H), 7.74-7.63 (m, 2H), 7.04 (dd, J =16.32 , 5.73 Hz, 1H), 5.67 (bs, 1H), 5.24-5.11 (m, 2H), 4.02 (dd, J =12.35, 4.41 Hz, 1H), 3.84-3.44 (m, 4H), 2.47-2.25 ( m, 2H), 2.14-2.01 (m, 3H); LCMS (ESI): m/z 375.1 (M+H).

Example 113

Synthesis of Compound 113

Step 1.

2,4-dichloropyrimidine (116 mg, 0.78 mmol), 4-bromoisoindolin-1-one (150 mg, 0.71 mmol), K ₂ CO ₃ (196 mg, 1.41 mmol) in DMF (3 mL) ) was degassed and purged 3 times with N ₂ , then the mixture was stirred at 80° C. for 14 h under an inert atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. Purification by pre-TLC (SiO ₂ , petroleum ether/ethyl acetate = 3:1) provided 9 (80 mg) as a pale yellow solid, which was used directly in the next step without further purification.

Step 2.

A mixture of 9 (80 mg, 0.13 mmol), pyridin-3-ol (14.6 mg, 0.15 mmol) and Cs ₂ CO ₃ (83 mg, 0.26 mmol) in DMF (3 mL) was degassed and washed 3 times with N ₂ Then, the mixture was stirred at 50° C. for 1 h under an inert atmosphere. The reaction mixture was filtered, then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (3 x 15 mL) and saturated brine (2 x 20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue which was pre-HPLC (HCl, 0.05 mL). % HCl-ACN) to give compound 113 (13.9 mg, 28%) as an orange solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.89 (s, 1H), 8.69-8.68 (d, 1H), 8.60-8.58 (d, 1H), 8.26-8.24 (m, 2H), 8.00-7.98 ( d, 1H), 7.90-7.85 (m, 2H), 7.58-7.54 (m, 1H), 4.88 (s, 2H); LCMS (ESI): m/z 383.0 (M+H).

Example 114

Synthesis of Compound 114

Step 1.

A solution of 3-hydroxypyridine (3.06 g, 32.2 mmol) in DMF (100 mL) was cooled to 0 °C and NaH (773 mg, 32.22 mmol) was added. The mixture was stirred 30 min at 0 °C, warmed to 15 °C and then 2 (4.0 g, 26.9 mmol) was added. The reaction mixture was stirred for a further 3 hours. Upon completion water (100 mL) was added and the resulting mixture was extracted with EtOAc (90 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. Purification by silica gel chromatography (petroleum ether: EtOAc = 50:1 to 20:1) gave 10 (2.2 g, 37%).

Step 2.

A solution of 1 (97 mg, 0.053 mmol) in DMF (4 mL) was cooled to 0 °C and NaH (13.9 mg, 0.058 mmol) was added. The mixture was stirred 30 min at 0° C. then 10 (100 mg, 0.48 mmol) was added. The solution was stirred at 0 °C for 15 h. The resulting mixture was poured into water (20 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by pre-HPLC (0.04% NH ₃ .H ₂ O/ACN/H ₂ O system) gave compound 114 (20 mg) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.56 (d, 1H), 8.51-8.46 (m, 2H), 8.06 (d, 1H), 7.88-7.82 (m, 1H), 7.81-7.67 (m, 3H), 7.50 (dd, 8.2 Hz, 1H), 7.09 (d, 1H), 5.17 (s, 2H); LCMS (ESI+): m/z 341 (M+H).

Example 115

Synthesis of Compound 115

Step 1.

To a mixture of 6-methyl-2,4-dichloropyrimidine (162 mg, 0.994 mmol) and 1 (185 mg, 1.1 mmol) in anhydrous CH ₃ CN (4 mL) was added K ₂ CO ₃ (274 mg, 2 mmol). ) was added and the mixture was stirred at 80° C. for 3 h. Concentrated under reduced pressure to give 11 (130 mg), which was used in the next step without further purification.

Step 2.

A solution of 11 (130 mg crude material), pyridin-3-ol (26 mg, 0.28 mmol), t-BuONa (45 mg, 0.47 mmol) and Xantphos (13.5 mg, 0.023 mmol) in anhydrous dioxane (3 mL) To this was added Pd ₂ (dba) ₃ (21 mg, 0.023 mmol). The mixture was stirred at 100° C. for 12 h under an inert atmosphere, filtered and then concentrated under reduced pressure. Purification by pre-HPLC (0.04%HCl/CH ₃ CN/H ₂ O system) gave compound 115 (3.6 mg, 2.1%) as the HCl salt. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.74 (s, 1H), 8.60 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.71-7.65 (m, 4H), 6.79 (m, 1H), 5.03 (s, 2H), 2.46 (s, 3H); LCMS (ESI): m/z 355.0 (M+H).

Example 116

Synthesis of Compound 116

10 (123 mg, 0.59 mmol), 2,3-dihydro-5-methoxy-1,1-dioxo-1,2-benzisothiazole (96 mg, 0.48 mmol) in anhydrous DMSO (2 mL) and CsF (146 mg, 0.96 mmol) was added cesium carbonate (314 mg, 0.96 mmol). The resulting mixture was degassed and stirred at 80° C. for 3 h under an inert atmosphere. Upon completion the mixture was filtered. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 116 (3.5 mg, 1.4%) as the HCl salt. ¹ H NMR (methanol- d ₄ , 400 MHz) δ 9.08 (s, 1H), 8.74 (d, 1H), 8.53 (d, 1H), 8.10-8.07 (q, 1H), 7.77 (d, 1H), 7.23 -7.14 (m, 3H), 5.03 (s, 2H), 3.93 (s, 3H); LCMS (ESI): m/z 371.0 (M+H).

Example 117

Synthesis of Compound 117

Compound 117 was synthesized in a similar manner to compound 116 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.81 (s, 1H), 8.65-8.63 (d, 1H), 8.57-8.56 (d, 1H), 8.29-8.28 (d, 1H), 8.14-8.13 ( d, 1H), 7.87-7.85 (d, 1H), 7.78-7.72 (m, 3H), 7.60-7.58 (m, 1H), 4.98 (s, 2H); LCMS (ESI): m/z 305.1 (M+H).

Example 118

Synthesis of Compound 118

Compound 118 was synthesized in a similar manner to compound 116 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.86 (s, 1H), 8.68-8.67 (d, 1H), 8.43-8.41 (d, 1H), 8.20-8.18 (t, 1H), 7.83-7.81 ( t, 1H), 7.18-7.07 (m, 3H), 6.58-6.55 (m, 1H), 4.85-4.80 (d, 2H), 4.54 (s, 1H), 2.25-2.16 (d, 3H); LCMS (ESI): m/z 305.1 (M+H).

Example 119

Synthesis of Compound 119

Compound 119 was synthesized in a similar manner to compound 116 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 9.08 (s, 1H), 8.74 (d, 1H), 8.53 (d, 1H), 8.10-8.07 (q, 1H), 7.77 (d, 1H), 7.23 -7.14 (m, 3H), 5.03 (s, 2H), 3.93 (s, 3H); LCMS (ESI): m/z 371.0 (M+H).

Example 120

Synthesis of Compound 120

10 (150 mg, 0.72 mmol), 2-oxindole (125 mg, 0.94 mmol), tBuONa (139 mg, 1.44 mmol), Ruphos (67 mg, 0.144 mmol) and Pd(OAc) in dioxane (2 mL) A mixture of ₂ (32 mg, 0.144 mmol) was degassed and stirred at 100° C. for 12 h under inert atmosphere. Upon completion the mixture was filtered and concentrated under reduced pressure. Purification by pre-HPLC (0.04% HCl/CH ₃ CN/H ₂ O system) gave compound 120 (1 mg) as a yellow oil ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.68 (s, 2H) , 8.25 (d, 1H), 7.93 (d, 1H), 7.69–7.66 (m, 1H), 6.79–6.75 (m, 2H), 6.64 (d, 1H), 6.53 (d, 1H), 6.51 (d) , 1H), 6.45 (d, 1H), 3.50 (s, 2H); LCMS (ESI): m/z 305.1 (M+H).

Example 121

Synthesis of Compound 121

Step 1.

2-bromo-6-fluoropyridine (500 mg, 2.84 mmol), pyridin-3-ol (297 mg, 3.13 mmol), cesium carbonate (1.85 g, 5.68 mmol) and CsF (22 mg, 142 mmol) was stirred at 120° C. for 2 h. Upon completion water (40 mL) was added and the reaction mixture was extracted with EtOAc (90 mL). The organic phase was washed with brine (50 mL), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give 12 (700 mg).

Step 2.

12 (100 mg, 0.40 mmol), 1 (67 mg, 0.40 mmol), potassium carbonate (55 mg, 0.40 mmol), CuI (3.8 mg, 0.019 mmol), and L-proline (2.3 mg, 0.019 mmol) was stirred at 110° C. for 16 h under an inert atmosphere. Upon completion water (40 mL) was added and the reaction mixture was extracted with EtOAc (90 mL). The organic phase was washed with brine (50 mL) and concentrated under reduced pressure. Purification by pre-HPLC (0.075% TFA/CH ₃ CN/H ₂ O system) gave compound 121 (40 mg, 29%) as a yellow solid and TFA salt. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.69-8.68 (d, 1H), 8.53-8.52 (d, 1H), 7.99-7.94 (m, 3H), 7.77 (m, 1H), 7.67-7.62 ( m, 3H), 7.07-7.05 (d, 1H), 6.83-6.81 (d, 1H), 4.95 (s, 2H); LCMS (ESI): m/z 340.1 (M+H).

Example 122

Synthesis of Compound 122

Compound 122 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.84 (s, 1H), 8.33-8.31 (d, 1H), 8.04-8.00 (t, 1H), 7.82-7.80 (m, 1H), 7.68-7.64 ( m, 1H), 7.56-7.54 (d, 2H), 6.94-6.93 (d, 1H), 4.80 (s, 2H); LCMS (ESI): m/z 304.0 (M+H).

Example 123

Synthesis of Compound 123

Compound 123 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.20 (s, 1H), 7.90-7.88 (d, 1H), 7.79-7.77 (t, 1H), 7.71-7.67 (m, 2H), 7.58-7.55 ( m, 2H), 7.38-7.35 (t, 1H), 7.16-7.15 (d, 1H), 7.04 (s, 1H), 5.15 (s, 2H); LCMS (ESI): m/z 373.0 (M+H).

Example 124

Synthesis of Compound 124

Compound 124 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.26-8.25 (d, 1H), 8.02-8.00 (d, 1H), 7.83-7.71 (m, 1H), 7.69-7.61 (m, 4H), 7.43- 7.40 (m, 2H), 7.42-7.38 (d, 1H), 7.13-7.11 (d, 1H), 5.17 (s, 2H); LCMS (ESI): m/z 373.0 (M+H).

Example 125

Synthesis of Compound 125

Compound 125 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.30 (d, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.71-7.69 (m, 3H), 7.45-7.43 (m, 3H) , 7.09–7.06 (m, 2H), 5.17 (s, 2H); LCMS (ESI): m/z 373.0 (M+H).

Example 126

Synthesis of Compound 126

Compound 126 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.99-7.98 (d, 1H), 7.87-7.85 (d, 1H), 7.77-7.75 (d, 1H), 7.68-7.65 (m, 2H), 7.42 ( m, 1H), 7.38-7.37 (m, 1H), 5.08 (s, 2H), 4.76-4.69 (m, 1H), 2.49-2.47 (m, 2H), 2.17-2.12 (m, 2H), 1.75- 1.88 (m, 2H); LCMS (ESI): m/z 317.0 (M+H).

Example 127

Synthesis of Compound 127

Compound 127 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 9.06 (bs, 1H), 8.90 (d, J =7.94 Hz, 1H), 8.83 (d, J =2.65 Hz, 1H), 8.75 (d, J = 9.26 Hz, 1H), 8.69 (d, J =5.29 Hz, 1H), 8.51 (d, J =2.65 Hz, 1H), 8.36 (dd, J =8.82, 1.76 Hz, 1H), 5.44 (s, 2H) , 8.27 (dd, J =7.94, 5.73 Hz, 1H), 8.13 (dd, J =8.82, 5.29 Hz, 1H), 7.92 (dd, J =9.04, 2.87 Hz, 1H); LCMS (ESI): m/z 305.0 (M+H).

Example 128

Synthesis of Compound 128

Compound 128 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.86-7.84 (d, 1H), 7.78-7.74 (m, 1H), 7.69-7.63 (m, 2H), 6.73 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 5.05 (s, 2H), 2.54-2.52 (m, 2H), 2.32 (s, 3H), 2.14-2.09 (m, 2H), 1.85-1.71 (m, 2H); LCMS (ESI): m/z 331.1 (M+H).

Example 129

Synthesis of Compound 129

Compound 129 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.41-8.39 (d, 1H), 8.02-8.01 (d, 1H), 7.87-7.85 (d, 1H), 7.69-7.65 (m, 2H), 7.55- 7.53 (m, 1H), 7.43-7.40 (m, 1H), 5.10 (s, 2H), 4.79-4.75 (m, 1H), 2.52-2.49 (m, 2H), 2.19-2.14 (m, 2H), 1.90-1.72 (m, 2H); LCMS (ESI): m/z 281.1 (M+H).

Example 130

Synthesis of Compound 130

Compound 130 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 8.64-8.61 (d, 1H), 8.23-8.22 (d, 1H), 7.88-7.86 (d, 1H), 7.70-7.68 (m, 2H), 7.61- 7.57 (m, 2H), 7.36-7.34 (m, 1H), 7.17-7.15 (m, 1H), 7.06 (s, 1H), 6.98-6.96 (d, 1H), 5.16 (s, 2H); LCMS (ESI): m/z 337.0 (M+H).

Example 131

Synthesis of Compound 131

Compound 131 was synthesized in a similar manner to compound 121 . ¹ H NMR (methanol- d ₄ , 400 MHz) δ 7.86-7.84 (d, 1H), 7.75-7.73 (m, 1H), 7.64-7.60 (m, 2H), 7.41-7.38 (m, 2H), 7.20- 7.17 (m, 2H), 7.04 (s, 1H), 6.54 (s, 1H), 4.87 (s, 2H), 2.40 (s, 3H); LCMS (ESI): m/z 387.0 (M+H).

Example 132

Synthesis of Compound 132

Compound 132 was synthesized in a similar manner to compound 121 . ^1H NMR (DMSO- d ₆ , 400MHz) 8.70 (s, 1H), 8.58 (d, J=4.85 Hz, 1H), 8.37 (d , J=2.65 Hz, 1H), 8.20-8.12 (m, 1H) , 7.98 (dd, J=8.82, 5.29 Hz, 1H), 7.78 (dd, J=9.04, 2.87 Hz, 1H), 7.63-7.53 (m, 2 =H), 7.41 (d, J=2.65 Hz, 1H) ), 7.36 (dd, J=8.60, 2.43 Hz, 1H), 5.08 (s, 2H). 3.92 (s, 1H); LCMS (ESI): m/z 370.0 (M+H).

Example 133

Synthesis of Compound 133

Compound 133 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.45-8.33 (m, 3H), 7.94-7.92 (d, 1H), 7.77-7.74 (dd, 1H), 7.49-7.45 (m, 3H), 7.42 ( s, 2H), 7.28-7.22 (dd, 1H), 5.11 (s, 1H), 3.90 (s, 3H); LCMS (ESI): m/z 370.0 (M+H).

Example 134

compound 134

Compound 134 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.59-8.57 (d, 1H), 8.29 (s, 1H), 7.83-7.81 (d, 1H), 7.68-7.60 (m, 3H), 7.56-7.55 ( d, 1H), 7.46-7.44 (d, 2H), 7.09-7.07 (d, 2H), 5.10 (s, 1H); LCMS (ESI): m/z 337.0 (M+H).

Example 135

Synthesis of Compound 135

Compound 135 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.91 (s, 1H), 8.78-8.77 (d, 1H), 8.69-8.68 (d, 1H), 8.23 (s, 2H), 8.13-8.11 (d, 1H), 7.89-7.86 (m, 1H), 7.66-7.63 (m, 1H), 6.86 (s, 1H), 4.80 (s, 2H), 2.45 (s, 3H); LCMS (ESI): m/z 319.1 (M+H).

Example 136

Synthesis of Compound 136

Compound 136 was synthesized in a similar manner to compound 121 . ¹ H NMR (DMSO- d ₆ , 400 MHz)) δ 8.87 (s, 1H), 8.65 (s, 1H), 8.20-8.19 (d, 1H), 7.97-7.95 (d, 1H), 7.81-7.78 (m , 2H), 7.68–7.65 (m, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 4.97 (s, 2H), 2.41 (s, 3H); LCMS (ESI): m/z 354.0 (M+H).

Example 137

Synthesis of Compound 137

Step 1.

A mixture of 13 (500 mg, 2.43 mmol), 4-chlorophenol (312 mg, 2.43 mmol), Cs ₂ CO ₃ (1.58 g, 4.85 mmol) and CsF (369 mg, 2.43 mmol) in DMF (30 mL) Degassed and purged with N ₂ (3X). The mixture was stirred at 100 °C for 12 h, then cooled and poured into water (100 mL). The solution was extracted with ethyl acetate (3 x 40 mL), and the organic layer was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by pre-TLC (petroleum ether:ethyl acetate = 1:1) to give 14 (380 mg) as a pale yellow solid.

Step 2.

14 (200 mg, 0.70 mmol), 1 (143 mg, 0.84 mmol), Cs ₂ CO ₃ in dioxane (2 mL) (459 mg, 1.41 mmol), CuI (40 mg, 0.21 mmol) and 2-(dimethylamino)acetic acid hydrochloride (30 mg, 0.21 mmol) was degassed and purged with N ₂ (3X). The mixture was stirred at 100° C. under N ₂ atmosphere for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL), adjusted to pH=7 with 2N HCl and separated. The aqueous layer was extracted with ethyl acetate (2 x 40 mL) and the combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 15 (230 mg) as a pale yellow solid.

Step 3.

Compound 15 (210 mg, 0.50 mmol), methylamine hydrochloride (41 mg, 0.60 mmol), EDCI (126 mg, 0.65 mmol), HOBt (89 mg, 0.65 mmol) and Et ₃ in CH ₂ Cl ₂ (30 mL). A mixture of N (102 mg, 1.01 mmol) was degassed and purged with N ₂ (3X). The mixture was stirred at 15 °C for 12 h. The solution was extracted with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by pre-HPLC to give compound 137 (1045 mg, 44%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.81 (d, 1H), 8.01 (d, 1H), 7.83-7.77 (m, 1H), 7.74-7.65 (m, 2H), 7.49 (d, 2H) , 7.42 (s, 1H), 7.33 (d, 2H), 7.06 (s, 1H), 5.04 (s, 2H), 2.81 (d, 3H); LCMS (ESI): m/z 430.0 (M+H).

Example 138

Synthesis of Compound 138

Step 1.

A mixture of compound 16 (500 mg, 3.07 mmol), 4-chlorophenyl (394 mg, 3.07 mmol), Cs ₂ CO ₃ (2.00 g, 6.14 mmol) and CsF (466 mg, 3.07 mmol) in DMF (8 mL). was degassed and purged with N ₂ (3X). The mixture was stirred at 100 °C for 12 h then poured into water (80 mL). The solution was extracted with ethyl acetate (3 x 40 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 17 (650 mg) as a dark brown oil.

Step 2.

Compound 17 (300 mg, 1.18 mmol), 1 (240 mg, 1.42 mmol), Cs ₂ CO ₃ (769 mg, 2.36 mmol), CuI (67 mg, 0.35 mmol) and 2-( in dioxane (20 mL) The mixture of dimethylamino)acetic acid hydrochloride (49 mg, 0.354 mmol) was degassed and purged with N ₂ three times. The mixture was stirred at 100 °C for 12 h, filtered and diluted with ethyl acetate (50 mL). The solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 18 as a dark brown oil, which was used without further purification.

Step 3.

To a solution of 18 (520 mg, 1.34 mmol) and Et ₃ N (271 mg, 2.68 mmol) in CH ₂ Cl ₂ (30 mL) at 0 °C was added acetyl chloride (116 mg, 1.47 mmol) dropwise. The mixture was stirred at 15 °C for 2 h then quenched with saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by pre-HPLC to give compound 138 (73 mg, 12.14%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 10.58 (s, 1H), 8.06-7.97 (m, 1 H), 7.83-7.77 (m, 1H), 7.74-7.64 (m, 2H), 7.49 (d , 2H), 7.41 (s, 1H), 7.28 (d, 2H), 6.98 (s, 1H), 4.98 (s, 2H), 2.08 (s, 3H); LCMS (ESI): m/z 430.0 (M+H).

Example 139

Synthesis of Compound 139

15 ( _210.00 mg), dimethylamine hydrochloride (49 mg, 0.60 mmol), EDCI (125 mg, 0.65 mmol), HOBt (88 mg, 0.65 umol) and Et ₃ N (102 mg) in CH ₂ Cl 2 (20 mL). mg, 1.01 mmol) was degassed and purged with N ₂ (3X). The mixture was stirred at 15° C. for 12 h, then washed with water (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by pre-HPLC to give compound 139 (13 mg, 6%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.09 (d, 1H), 7.89-7.84 (m, 1H), 7.77-7.69 (m, 2H), 7.51 (d, 2H), 7.36 (d, 2H) , 7.13 (s, 1H), 5.22 (s, 2H), 2.95 (s, 3H), 2.89 (s, 3H); LCMS (ESI): m/z 445.0 (M+H).

Example 140

Synthesis of Compound 140

Step 1.

A mixture of 19 (120 mg, 0.56 mmol), pyridin-3-ol (53 mg, 0.56 mmol), Cs ₂ CO ₃ (0.36 mg, 1.11 mmol) and CsF (84 mg, 0.56 umol) in DMF (2 mL). was degassed and purged with N ₂ (3X). The mixture was stirred at 100 °C for 12 h then poured into water (80 mL). The reaction mixture was extracted with ethyl acetate (3 x 40 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 20 (160 mg) as a pale yellow oil.

Step 2.

20 (160 mg, 0.58 mmol), 1 (99 mg, 0.58 mmol), Cs ₂ CO ₃ (380 mg, 1.17 mmol), CuI (33 mg, 0.17 mmol) and 2- (dioxane) in dioxane (2 mL) A mixture of methylamino)acetic acid hydrochloride (24 mg, 0.17 mmol) was degassed and purged with N ₂ (3X). The mixture was stirred at 100 °C for 12 h, then filtered and concentrated. The crude material was purified by pre-HPLC to give compound 140 (27 mg, 10%) as a white solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.98 (s, 1H), 8.74 (d, 1H), 8.34 (d, 1H), 7.99 (d, 1H), 7.92 (dd, 1H), 7.85-7.79 (m, 1H), 7.71-7.66 (m, 2H), 7.34 (s, 1H), 7.21 (s, 1H), 5.10 (s, 2H); LCMS (ESI): m/z 408.0 (M+H).

Example 141

Synthesis of Compound 141

Compound 141 was synthesized in a similar manner to compound 140. ^1H NMR ( DMSO- d ₆ 400 MHz) δ 8.05 (d, 1H), 7.88-7.82 (m, 1H), 7.77-7.68 (m, 2H ) , 6.99 (d, 2H), 5.22 (br. s. , 2H), 5.14 (br. s., 1H), 2.80 (d, 4H); LCMS (ESI): m/z 421.0 (M+H).

Example 142

Synthesis of Compound 142

Step 1.

To a mixture of 2,6-dichloropyrazine (193 mg, 1.30 mmol) and 1 (200 mg, 1.18 mmol) in DMF (5 mL) was added Cs ₂ CO ₃ (770 mg, 2.36 mmol). The resulting mixture was stirred at 100 °C for 5 h. The mixture was cooled to 25° C. and poured into ice water. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by TLC (petroleum ether/ethyl acetate = 2:1) to give 21 (220 mg, 60%) as a yellow solid.

step. 2

To a mixture of 21 (220 mg, 0.78 mmol) and pyridin-3-ol (74 mg, 0.78 mmol) in DMF (3 mL) was added Cs ₂ CO ₃ (509 mg, 1.56 mmol) in one portion. The mixture was stirred at 50 °C for 1 h, cooled to 25 °C and poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by pre-HPLC to give compound 142 (22 mg, 13%) as a yellow solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.95 (s, 1H); 8.71-8.70 (d, 1H), 8.40-8.37 (d, 2H), 8.32-8.30 (d, 1H), 8.01-8.00 (d, 1H), 7.89-7.82 (m, 2H), 7.72-7.70 (m) , 2H), 5.25-5.15 (m, 2H); LCMS (ESI+): m/z 341 (M+1).

Example 143

Synthesis of Compound 143

Step 1.

To a solution of compound 22 (100 mg, 0.61 mmol) and Et ₃ N (123 mg, 1.22 mmol) in anhydrous THF (15 mL) at 0 °C was added 4-chlorophenol (78 mg, 0.61 mmol). The mixture was stirred at 15 °C for 1 h and then concentrated to give 23 (180 mg) as a pale yellow solid.

Step 2.

A mixture of 23 (180 mg, 0.70 mmol), 1 (60 mg, 0.35 mmol), CsF (107 mg, 0.70 mmol), Cs ₂ CO ₃ (458 mg, 1.41 mmol) in DMF (3 mL) was degassed with N It was purged with ₂ (3X). The mixture was stirred at 80 °C for 1 h, filtered and then purified by pre-HPLC to give compound 143 (15 mg, 5%) as a pale yellow solid. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 7.97 (d, 1H), 7.81 (s, 1H), 7.72 (d, 1H), 7.43 (s, 1H), 7.31 (s, 2H), 7.18 (s , 2H), 5.09 (s, 2H), 2.33 (s, 3H); LCMS (ESI): m/z 356.0 (M+H).

Example 144

Synthesis of Compound 144

Compound 144 was synthesized in a similar manner to compound 143 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.02 (d, 1H), 7.86-7.81 (m, 1H), 7.75 (d, 1H), 7.72-7.65 (m, 1H), 7.53 (d, 2H) , 7.38 (d, 2H), 5.15 (br. s., 2H), 2.45 (s, 3H); LCMS (ESI): m/z 389.0 (M+H).

Example 145

Synthesis of Compound 145

Compound 145 was synthesized in a similar manner to compound 143 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.86 (s, 1 H), 8.04 (d, 1 H), 7.88-7.81 (m, 1 H), 7.79-7.67 (m, 2 H), 7.54 ( d, 2 H), 7.40 (d, 2 H), 5.17 (br. s., 2 H); LCMS (ESI): m/z 375.0 (M+H).

Example 146

Synthesis of Compound 146

Compound 146 was synthesized in a similar manner to compound 143 . ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 8.91 (s, 1 H), 8.80 (d, 1 H), 8.65 (d, 1 H), 8.10 (d, 1 H,) 8.04 (d, 1 H) ), 7.88-7.82 (m, 1 H), 7.77-7.68 (m, 3 H), 5.18 (s, 2 H); LCMS (ESI): m/z 342.0 (M+H).

biological Example

Example 147

GPR120 β- austin Recruitment test

This in vitro assay tests the ability of compounds to activate intracellular signaling through β-arrestin recruitment to heterologously expressed human GPR120. This functional cellular assay utilizes enzyme fragment complementation with β-galactosidase (β-gal) as a functional reporter (DiscoveRx PathHunter® β-Arrestin Assay Platform). The human GPR120 receptor (GenBank accession number NM_181745) was fused in frame with the small enzyme fragment ProLink ^™ and co-expressed with the fusion protein of the larger, N-terminal deletion mutants of β-arrestin 2 and β-gal in CHO-K1 cells . Activation by the GPR120 agonist stimulates the binding of β-arrestin to the ProLink-tagged GPCR and forces complementation of the two enzyme fragments, resulting in the formation of an active β-gal enzyme. This interaction leads to an increase in enzyme activity that can be measured using chemiluminescent PathHunter® detection reagents.

One day prior to the assay, cells were seeded in white walled 384-well microplates with a total volume of 20 μl of growth medium and incubated overnight at 37° C./5% CO ₂ . On assay day, growth medium was removed and 20 μl assay buffer (HBSS + 10 mM HEPES + 0.1% heat-inactivated BSA) was added to each well.

Stock solutions were prepared by dissolving test compounds in 100% DMSO at a concentration of 10 mM. Serial dilutions were performed from the stock solution into assay buffer to obtain median concentrations 5-fold higher than the concentration to be tested. 5 μl of 5× compound solution was added to the cells and the assay plate was incubated at 37° C. for 90 minutes. Final concentrations of the compounds tested in the assay ranged from 1.5 nM to 100 μM. After incubation, 12.5 μl of PathHunter® Detection Reagent was added to each well and the plate was incubated at room temperature for 60 minutes. Chemiluminescence was read using an EnVision plate reader (PerkinElmer) and raw data were expressed as relative light units (RLU).

Non-linear least-squares curve fitting of the raw data (RLU) to measure agonist potency (EC ₅₀ values) was performed using a 4-parameter model with variable Hill Slope with the GraphPad Prism software package. :

The pEC ₅₀ values for compounds of Formula I in this assay (pEC ₅₀ =-log(EC ₅₀ ) from curve adjustment), β-Arr pEC50, are reported in Table 1 below. Alternatively, percent activation at a single concentration is reported.

Example 148

human GPR120 Calcium-release assay

This in vitro assay tests the ability of compounds to activate heterologously expressed human GPR120 through G-protein binding leading to the production of inositol 1,4,5-triphosphate and the fixation of intracellular calcium. This functional cellular assay is based on ^the luminescence of mitochondrial aequorin after intracellular Ca ²⁺ release. Aequorin is a photoprotein isolated from the jellyfish Aequorea victoria . Active proteins are formed in the presence of molecular oxygen from apoequorin and its cofactor coelenterazine. Binding of Ca ²⁺ to the active protein induces a conformational change, resulting in oxidation ^of coelenterazine and subsequent blue emission.

A short variant of the human GPR120 receptor (GenBank Accession No. AAI01176) was stably expressed in the CHO-K1 cell line co-expressing Gα16 and mitochondrial aequorin.

Cells were grown to mid-log phase in antibiotic-free culture medium, detached with PBS/EDTA, centrifuged and cultured in assay buffer (DMEM-F12 medium supplemented with 15 mM HEPES pH 7.0 and 0.1% protease-free BSA). ) at a concentration of 10 ⁶ cells/ml. Cells were incubated with 5 μM coelenterazine h for at least 4 hours at room temperature.

Stock solutions were prepared by dissolving test compounds in 100% DMSO at a concentration of 20 mM. Serial dilutions in 100% DMSO from the stock solution were performed to obtain median concentrations 200 times higher than the concentration to be tested. Each sample was diluted 100-fold in assay buffer. 50 μl of this compound solution was dispensed into each well of a 96-well assay plate. Final concentrations of the compounds tested in the assay ranged from 5 nM to 100 μM. α-Linolenic acid was used as a reference compound. Each test was performed in duplicate.

To start the assay, 50 μl of cell suspension was added to each well of the assay plate. The resulting luminescence was recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000) and the raw data were expressed as relative light units (RLU).

To measure agonist potency (EC ₅₀ values), nonlinear least-squares curve fitting of the raw data (RLU) was performed with the GraphPad Prism software package, using a 4-parameter model with variable slope slopes:

The pEC ₅₀ values (pEC ₅₀ =-log(EC ₅₀ ) from curve adjustment), Ca2+ pEC50, for representative compounds of Formula I in this assay are reported in Table 1 below.

Activity of Compounds of Formula I in In Vitro Assays Compound # β- Arr pEC50 Ca2 + pEC50 One 5.1 5.1 2 18% @ 10uM 3 < 4.5 4 < 4.5 5 < 5.0 6 < 5.0 7 4.9 8 4.9 9 < 4.5 10 < 4.5 11 < 5.0 12 < 4.5 13 9%@10uM 14 8%@10uM 15 3% @ 10uM 16 5.2 5.9 17 4% @ 10uM 18 <5 19 5.3 6.1 20 5.2 5.4 21 <5.1 6.3 22 5.8 < 4.0 23 5.5 24 1% @ 10uM 25 16% @ 10uM 26 4.9 27 9%@10uM 28 4.9 29 4.8 30 17% @ 10uM 31 11% @ 10uM 32 4.6 33 5.1 <4 34 5.8 6.7 35 5.8 < 4.0 36 6.2 5.1 37 6 6.7 38 4.8 39 < 5.0 40 < 5.0 41 5.6 6.1 42 6 6.5 43 < 4.5 44 < 5.0 5.8 45 5.8 < 4.0 46 5.3 47 5.2 48 < 5.0 49 5.6 50 5.3 5.2 51 5 6 52 4.9 53 < 5.0 54 < 5.0 55 < 5.0 56 < 5.0 6.1 57 6 58 5.6 6.2 59 5.2 4.9 60 5.8 6.3 61 < 4.5 < 4.0 62 < 5.0 63 6.3 < 4.0 64 < 5.0 65 < 5.0 66 < 5.0 67 < 5.0 5.2 68 5.6 69 5.4 70 4.8 71 1% @ 10uM 72 < 5.0 < 4.0 73 < 5.0 74 < 4.5 75 < 4.5 76 < 4.5 77 5.6 6 78 5.8 5.4 79 5.8 6.3 80 6.3 5.6 81 5.2 82 5.6 5.9 83 5.6 6.1 84 < 5.0 85 < 4.5 86 6.6 6.4 87 6.1 5.8 88 < 5.0 89 5.6 4.7 90 4.9 91 5.4 92 5.5 93 5.1 6.2 94 < 5.0 95 6.4 96 6 < 5.0 97 6.2 6 98 6.1 5.6 99 6.3 6.8 100 6.8 101 6.4 < 7.0 102 6.1 103 5.7 104 5.4 105 5.6 106 6 6.7 107 6.1 108 < 4.5 109 < 4.5 110 < 4.5 111 < 5.0 112 < 4.5 113 4.9 114 4.9 4.8 115 5.2 116 4.4 117 <5 118 6 119 4.5 120 < 4.5 121 5.8 6.7 122 <5 6.3 123 < 4.5 < 4.0 124 < 4.5 125 < 4.5 < 5.0 126 < 4.5 127 < 4.5 128 7.4 7.1 129 < 4.5 130 < 4.5 131 6.8 6.5 132 < 4.5 133 < 4.5 134 5 135 < 5.0 136 6.2 137 5.6 138 5.5 139 < 5.0 140 6 141 5.2 142 4.4 5.9 143 < 4.5 144 5.7 145 5.1 146 4.8

The results show that the compounds of the invention, as exemplified in the above examples and generally defined by formula 1, are potent GPR120 agonists to be applied in the treatment of T2D. Alternatively, as disclosed in the detailed description above, these compounds can be administered via any route of administration and at varying frequencies, and in one preferred embodiment, these compounds are purified for the treatment and control of the disease in patients with T2D. or administered orally once daily in the form of a capsule.

Example 149

GPR120 C57BL /6J mouse oral glucose tolerance test

An oral glucose tolerance test (OGTT) was performed with specific compounds to determine the acute effects of compounds on glucose excursions.

Male C57BL/6J mice 8 to 10 weeks old and on a regular diet were used for the study. Ten mice were used per treatment group, and the body weight of each mouse on the study day ranged from 24 to 30 grams, with an average body weight of 27.2 to 27.3 grams for each treatment group.

Test articles were prepared by mixing and sonication at a concentration of 10 mg/mL as a suspension in a dosing vehicle (0.5% hydroxypropyl methylcellulose and 2% Tween-20 in water).

Mice were fasted for 6 hours before administration of vehicle or test article at 100 mg/kg (10 mL/kg) by oral intake. Glucose was administered at 3 g/kg 30 minutes after administration of the test article (P0). Animals were bled via tail clipping to measure basal glucose levels 30 min before glucose challenge and again at 0, 15, 30, 60, 90 and 120 min after glucose challenge to measure glucose levels. Glucose levels of all blood samples were measured using a Johnson & Johnson One Touch Glucose Meter.

Glucose values were put into an excel sheet and mean values ± standard error of the mean were graphed in GraphPad Prism. The significance of differences between groups was analyzed by performing a two-way variate repeated measures for time course study. A P value of less than 0.05 was considered statistically significant.

Example 150

LPS - stimulated human peripheral blood mononuclear Anti-inflammatory activity in cells

The ability of compounds of the present invention to inhibit TNFα production was evaluated using human peripheral blood mononuclear cells (hPBMCs), which synthesize and secrete TNFα when stimulated with lipopolysaccharide (LPS).

Packs of mononuclear cells collected by and purchased from Key Biologics were used for the preparation of hPBMCs. Briefly, the cell product was sterilized from the phoresis bag, carefully layered on pre-warmed Ficoll (Histopaque 1077), and centrifuged at 1,800xg for 15 minutes at room temperature without brake. After centrifugation, the interface was removed and added to sterile Dulbecco's Phosphate Buffered Saline (DPBS). Cells were then pelleted at 300x g for 10 min at room temperature. Cells were resuspended in fresh DPBS and then pelleted again to minimize platelet contamination. Subsequently, the pellet was resuspended in DPBS and cells were counted. Cells were re-pelletized and cryopreserved at 1 x 10 ⁸ cells per ml in DMEM/30% FBS/10% DMSO. For all hPBMCs, individual donors were kept separate throughout the procedure. For the assay, hPBMCs were seeded at 500,000 cells/well in 80 μl assay medium (DMEM, 0.1% FBS, 1% penicillin/streptomycin) in a flat bottom 96-well plate and left to recover for 1 hour in a 37°C incubator. After allowing, the compound was added.

Compounds were dissolved from powder as 20 mM stocks in 100% DMSO and then serially diluted in assay medium to prepare 10× stocks to make 5 concentrations in the assay (100 μM, 30 μM, 10 μM, 3 μM and 1 μM). All compound dilutions were added to the plate containing hPBMCs (10 μl for a final assay volume of 100 μl) and incubated for 1 hour at 37° C. before the addition of stimulants. Control wells received 10 μl of vehicle (medium containing 5% DMSO).

For LPS challenge, a 1 mg/ml stock solution of lipopolysaccharide (LPS) was diluted 1000-fold with assay medium (10 μl LPS + 10 ml medium). 10 μl of LPS was added to all wells except for the “unstimulated” control wells. "Non-stimulated" control wells received 10 μl of medium. Plates were incubated at 37° C. for 4 hours. After 4 hours, the plate was centrifuged at 1,200 rpm for 5 minutes and the culture medium supernatant was collected in a fresh 96-well plate.

TNFa levels in culture supernatants were measured by immunoassay using the Meso Scale Diagnostics Electrochemiluminescence Immunoassay System. Meso Scale V-plex 96-well plates (Meso Scale Diagnostics, Rockville, MD) were used as directed by the manufacturer (overnight incubation protocol) for detection of TNFα. Samples were diluted 100-fold. TNFα concentrations were determined by interpolation against a standard curve and then multiplied by 100 to obtain a “pg/ml” value. TNFα release was reported as % of vehicle treated with LPS-stimulated cells.

While specific embodiments have been illustrated and described, it will be appreciated that changes and modifications may be made therein according to ordinary skill without departing from the broader aspects of the invention as defined in the claims that follow.

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Claims (21)

A compound of the formula selected from: or a tautomer thereof, or an isotopic isomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, respectively, or a pharmaceutically acceptable solvent of each of the foregoing. compound:

In the above formula,
W is O;
each X is independently CH, CR ₃ or N, where R ₃ is halogen, alkyl, alkoxy, or CN;
Y is SO ₂ , or CO;
Z is -CH ₂ -, -CH(CH ₃ )-, or -C(CH ₃ ) ₂ -;
R ₁ is -C(O)NH ₂ , -C(O)NH-phenyl, an alkyl group optionally substituted with halogen, cycloalkyl, aryl, or heteroaryl, 1 to 3 halogens, -C(O)CH ₃ , -SO ₂ CH ₃ , or a 3-7 membered cycloalkyl or heterocyclyl group optionally substituted with alkyl, or halogen, CN, alkoxy, -OCF ₃ , -CF ₃ , -N(CH ₃ ) ₂ , an aryl or heteroaryl group optionally substituted with 1 to 3 groups independently selected from -NHC(O)CH ₃ , alkyl, -O-phenyl, -OCH ₂ -phenyl, or heteroaryl; and
R ₂ is H, halogen, CN, OCH ₃ , OCF ₃ , NH-acyl, an alkyl group optionally substituted with 1 to 3 halogens, a carboxamide or sulfonamido group optionally substituted with alkyl, an alkyl group optionally substituted with cycloalkyl, or heterocyclyl groups substituted with, or aryl or heteroaryl groups optionally substituted with alkoxy. A compound of the structure:

A pharmaceutical composition for reducing neuroinflammation in a mammal, comprising the compound of claim 1 or 2. A pharmaceutical composition for the treatment of diabetes, prediabetes or metabolic syndrome, or one or more symptoms of each of these, in a mammal, comprising a compound of claim 1 or 2. A pharmaceutical composition for treating steatohepatitis in a mammal, comprising a compound of claim 1 or 2. A pharmaceutical composition for the treatment of non-alcoholic steatohepatitis in a mammal comprising the compound of claim 1 or 2. A pharmaceutical composition comprising a compound of claim 1 or 2 for the treatment of a disorder associated with, leading to, or resulting from neuroinflammation in a mammal. A pharmaceutical composition comprising a compound of claim 1 or 2 for the treatment of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or multiple system atrophy, or one or more symptoms of each of these. delete delete delete delete delete delete delete delete delete delete delete delete delete